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De Risi M, Cavezza D, Torromino G, Capalbo A, Cundin XB, Di Martino R, Alvino FG, Iemolo A, Speranza L, Perrone-Capano C, Crispino M, Cirillo C, Luini A, Sacco F, Grumati P, De Leonibus E. Cortico-striatal circuit mechanisms drive the effects of D1 dopamine agonists on memory capacity in mice through cAMP/PKA signalling. Nat Commun 2025; 16:2615. [PMID: 40097401 PMCID: PMC11914583 DOI: 10.1038/s41467-025-57788-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 03/03/2025] [Indexed: 03/19/2025] Open
Abstract
Working memory capacity (WMC), the number of items remembered in a short-time interval, is regulated by fronto-striatal dopamine (DA) and is reduced in schizophrenia. We investigated how excessive and insufficient D1 dopamine receptor stimulation impairs and expands WMC, focusing on the cAMP/PKA pathway in the fronto-striatal circuit. Low doses of the D1 agonist SKF 38393 enhance WMC by activating the striatum (mice remember more objects), while high doses, paradoxically, impair WMC, activating the same pathway in the medial prefrontal cortex (mPFC) but inhibiting it in the striatum. This impairment, arising from mPFC-driven recruitment of inhibitory striatal parvalbumin interneurons, can be prevented by optogenetic inhibition of the mPFC-striatal pathway. Low doses of SKF 38393 also rescue WMC deficits in a schizophrenia mouse model. These results highlight the need for a systems pharmacology approach that considers complex brain interactions and intracellular signalling pathways, rather than isolated drug-receptor interactions, to develop memory-enhancing treatments.
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MESH Headings
- Animals
- Receptors, Dopamine D1/agonists
- Receptors, Dopamine D1/metabolism
- Prefrontal Cortex/drug effects
- Prefrontal Cortex/metabolism
- Prefrontal Cortex/physiology
- Cyclic AMP/metabolism
- Schizophrenia/physiopathology
- Schizophrenia/metabolism
- Schizophrenia/drug therapy
- Memory, Short-Term/drug effects
- Memory, Short-Term/physiology
- Signal Transduction/drug effects
- Mice
- Dopamine Agonists/pharmacology
- Cyclic AMP-Dependent Protein Kinases/metabolism
- Corpus Striatum/drug effects
- Corpus Striatum/metabolism
- Corpus Striatum/physiology
- Male
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology
- Mice, Inbred C57BL
- Optogenetics
- Interneurons/metabolism
- Interneurons/drug effects
- Disease Models, Animal
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Affiliation(s)
- Maria De Risi
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Monterotondo (Rome), Italy
- Telethon Institute of Genetics and Medicine (TIGEM), Telethon Foundation, Pozzuoli (Naples), Italy
| | - Diletta Cavezza
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Monterotondo (Rome), Italy
- PhD Program in Behavioral Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Giulia Torromino
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Monterotondo (Rome), Italy
- Department of Humanistic Studies, University of Naples Federico II, Naples, Italy
| | - Anita Capalbo
- Institute of Biochemistry and Cell Biology (IBBC), Naples, Italy
| | - Xabier Bujanda Cundin
- Telethon Institute of Genetics and Medicine (TIGEM), Telethon Foundation, Pozzuoli (Naples), Italy
| | | | - Filomena Grazia Alvino
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Monterotondo (Rome), Italy
| | - Attilio Iemolo
- Institute of Genetics and Biophysics (IGB), National Research Council (CNR), Naples, Italy
| | - Luisa Speranza
- Institute of Genetics and Biophysics (IGB), National Research Council (CNR), Naples, Italy
| | - Carla Perrone-Capano
- Institute of Genetics and Biophysics (IGB), National Research Council (CNR), Naples, Italy
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Marianna Crispino
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Carmine Cirillo
- Telethon Institute of Genetics and Medicine (TIGEM), Telethon Foundation, Pozzuoli (Naples), Italy
| | - Alberto Luini
- Institute of Biochemistry and Cell Biology (IBBC), Naples, Italy
| | - Francesca Sacco
- Telethon Institute of Genetics and Medicine (TIGEM), Telethon Foundation, Pozzuoli (Naples), Italy
| | - Paolo Grumati
- Telethon Institute of Genetics and Medicine (TIGEM), Telethon Foundation, Pozzuoli (Naples), Italy
| | - Elvira De Leonibus
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Monterotondo (Rome), Italy.
- Telethon Institute of Genetics and Medicine (TIGEM), Telethon Foundation, Pozzuoli (Naples), Italy.
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Bae JW, Yi JH, Choe SY, Li Y, Jung MW. Cortical VIP neurons as a critical node for dopamine actions. SCIENCE ADVANCES 2025; 11:eadn3221. [PMID: 39742499 DOI: 10.1126/sciadv.adn3221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 11/20/2024] [Indexed: 01/03/2025]
Abstract
Dopamine modulates a wide range of cognitive processes in the prefrontal cortex, but the underlying mechanisms remain unclear. Here, we examined the roles of prefrontal vasoactive intestinal polypeptide (VIP)-expressing neurons and their D1 receptors (D1Rs) in working memory using a delayed match-to-sample task in mice. VIP neurons conveyed robust working-memory signals, and their inactivation impaired behavioral performance. Moreover, selective knockdown of D1Rs in VIP neurons also resulted in impaired performance, indicating the critical role of VIP neurons and their D1Rs in supporting working memory. Additionally, we found that dopamine release dynamics during the delay period varied depending on the target location. Furthermore, dopaminergic terminal stimulation induced a contralateral response bias and enhanced neuronal target selectivity in a laterality-dependent manner. These results suggest that prefrontal dopamine modulates behavioral responses and delay-period activity based on laterality. Overall, these findings shed light on dopamine-modulated prefrontal neural processes underlying higher-order cognitive functions.
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Affiliation(s)
- Jung Won Bae
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Korea
| | - Jee Hyun Yi
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Korea
| | - Seo Yeon Choe
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Korea
| | - Yulong Li
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
| | - Min Whan Jung
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Korea
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
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Inagaki R, Kita S, Niwa N, Fukunaga K, Iwamoto T, Moriguchi S. Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD-like behavior in NCX3 heterozygous mice. FEBS J 2025; 292:426-444. [PMID: 39624860 PMCID: PMC11734882 DOI: 10.1111/febs.17339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/24/2024] [Accepted: 11/19/2024] [Indexed: 01/16/2025]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that involves dopaminergic dysfunction in the prefrontal cortex (PFC), manifesting hyperactivity, inattention, and cognitive deficits. However, the ADHD-associated candidate genes underlying dopaminergic neurotransmission alterations remain poorly defined. Here, we identified the abundant localization of sodium-calcium exchanger 3 (NCX3) levels in the dopaminergic neurons of the ventral tegmental area, a major source of dopaminergic innervation to the PFC. We confirmed that NCX3 knockdown in N27 cells caused aberrant dopamine influx through the strong interaction between calcium/calmodulin-dependent protein kinase II alpha and dopamine transporter. In addition, we assessed behavioral changes and underlying molecular properties in NCX3 heterozygous (NCX3+/-) mice. NCX3+/- mice exhibited hyperactivity, cognitive deficits, and social dysfunction which were alleviated by treating with methylphenidate. Furthermore, NCX3+/- mice displayed a persistent elevation of basal dopamine levels and decreased extracellular levels of dopamine triggered by social stimuli in the PFC of NCX3+/- mice. In agreement with the rise in extracellular dopamine levels in the PFC, NCX3+/- mice showed activation of dopamine D1 receptor signaling pathways in the PFC compared to wild-type mice. Thus, deficiency of NCX3 leads to impaired dopaminergic neurotransmission in the PFC, which likely accounts for the ADHD-like behavior in NCX3+/- mice.
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Affiliation(s)
- Ryo Inagaki
- Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Satomi Kita
- Department of Pharmacology, Faculty of Pharmaceutical SciencesTokushima Bunri UniversityJapan
| | - Nozomu Niwa
- Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Kohji Fukunaga
- Department of Pharmacology, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Takahiro Iwamoto
- Department of Pharmacology, Faculty of MedicineFukuoka UniversityJapan
| | - Shigeki Moriguchi
- Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
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Higa GSV, Viana FJC, Francis-Oliveira J, Cruvinel E, Franchin TS, Marcourakis T, Ulrich H, De Pasquale R. Serotonergic neuromodulation of synaptic plasticity. Neuropharmacology 2024; 257:110036. [PMID: 38876308 DOI: 10.1016/j.neuropharm.2024.110036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/15/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
Synaptic plasticity constitutes a fundamental process in the reorganization of neural networks that underlie memory, cognition, emotional responses, and behavioral planning. At the core of this phenomenon lie Hebbian mechanisms, wherein frequent synaptic stimulation induces long-term potentiation (LTP), while less activation leads to long-term depression (LTD). The synaptic reorganization of neuronal networks is regulated by serotonin (5-HT), a neuromodulator capable of modify synaptic plasticity to appropriately respond to mental and behavioral states, such as alertness, attention, concentration, motivation, and mood. Lately, understanding the serotonergic Neuromodulation of synaptic plasticity has become imperative for unraveling its impact on cognitive, emotional, and behavioral functions. Through a comparative analysis across three main forebrain structures-the hippocampus, amygdala, and prefrontal cortex, this review discusses the actions of 5-HT on synaptic plasticity, offering insights into its role as a neuromodulator involved in emotional and cognitive functions. By distinguishing between plastic and metaplastic effects, we provide a comprehensive overview about the mechanisms of 5-HT neuromodulation of synaptic plasticity and associated functions across different brain regions.
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Affiliation(s)
- Guilherme Shigueto Vilar Higa
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil; Departamento de Bioquímica, Instituto de Química (USP), Butantã, São Paulo, SP, 05508-900, Brazil
| | - Felipe José Costa Viana
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - José Francis-Oliveira
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Emily Cruvinel
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Thainá Soares Franchin
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Tania Marcourakis
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Henning Ulrich
- Departamento de Bioquímica, Instituto de Química (USP), Butantã, São Paulo, SP, 05508-900, Brazil
| | - Roberto De Pasquale
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil.
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Parlatini V, Bellato A, Murphy D, Cortese S. From neurons to brain networks, pharmacodynamics of stimulant medication for ADHD. Neurosci Biobehav Rev 2024; 164:105841. [PMID: 39098738 DOI: 10.1016/j.neubiorev.2024.105841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 07/25/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024]
Abstract
Stimulants represent the first line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) and are among the most prescribed psychopharmacological treatments. Their mechanism of action at synaptic level has been extensively studied. However, it is less clear how their mechanism of action determines clinically observed benefits. To help bridge this gap, we provide a comprehensive review of stimulant effects, with an emphasis on nuclear medicine and magnetic resonance imaging (MRI) findings. There is evidence that stimulant-induced modulation of dopamine and norepinephrine neurotransmission optimizes engagement of task-related brain networks, increases perceived saliency, and reduces interference from the default mode network. An acute administration of stimulants may reduce brain alterations observed in untreated individuals in fronto-striato-parieto-cerebellar networks during tasks or at rest. Potential effects of prolonged treatment remain controversial. Overall, neuroimaging has fostered understanding on stimulant mechanism of action. However, studies are often limited by small samples, short or no follow-up, and methodological heterogeneity. Future studies should address age-related and longer-term effects, potential differences among stimulants, and predictors of treatment response.
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Affiliation(s)
- Valeria Parlatini
- School of Psychology, University of Southampton, Southampton, United Kingdom; Centre for Innovation in Mental Health, University of Southampton, Southampton, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; Institute of Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom; Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom; Solent NHS Trust, Southampton, United Kingdom.
| | - Alessio Bellato
- School of Psychology, University of Southampton, Southampton, United Kingdom; Centre for Innovation in Mental Health, University of Southampton, Southampton, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; Solent NHS Trust, Southampton, United Kingdom; School of Psychology, University of Nottingham, Semenyih, Malaysia
| | - Declan Murphy
- Institute of Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom; Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom
| | - Samuele Cortese
- School of Psychology, University of Southampton, Southampton, United Kingdom; Centre for Innovation in Mental Health, University of Southampton, Southampton, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; Solent NHS Trust, Southampton, United Kingdom; Mind and Neurodevelopment (MiND) Research Group, University of Nottingham, Semenyih, Malaysia; Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York, NY, USA
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Kolesnikova TO, Demin KA, Costa FV, de Abreu MS, Kalueff AV. Zebrafish models for studying cognitive enhancers. Neurosci Biobehav Rev 2024; 164:105797. [PMID: 38971515 DOI: 10.1016/j.neubiorev.2024.105797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/16/2024] [Accepted: 07/03/2024] [Indexed: 07/08/2024]
Abstract
Cognitive decline is commonly seen both in normal aging and in neurodegenerative and neuropsychiatric diseases. Various experimental animal models represent a valuable tool to study brain cognitive processes and their deficits. Equally important is the search for novel drugs to treat cognitive deficits and improve cognitions. Complementing rodent and clinical findings, studies utilizing zebrafish (Danio rerio) are rapidly gaining popularity in translational cognitive research and neuroactive drug screening. Here, we discuss the value of zebrafish models and assays for screening nootropic (cognitive enhancer) drugs and the discovery of novel nootropics. We also discuss the existing challenges, and outline future directions of research in this field.
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Affiliation(s)
| | - Konstantin A Demin
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia; Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia
| | - Fabiano V Costa
- Neurobiology Program, Sirius University of Science and Technology, Sochi, Russia
| | - Murilo S de Abreu
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil; West Caspian University, Baku, Azerbaijan.
| | - Allan V Kalueff
- Neurobiology Program, Sirius University of Science and Technology, Sochi, Russia; Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia; Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia; Suzhou Key Laboratory on Neurobiology and Cell Signaling, Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China.
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Tanaka D, Yaguchi H, Yoshizaki K, Kudo A, Mori F, Nomura T, Pan J, Miki Y, Takahashi H, Hara T, Wakabayashi K, Yabe I. Behavioral and histological analyses of the mouse Bassoon p.P3882A mutation corresponding to the human BSN p.P3866A mutation. Front Neurosci 2024; 18:1414145. [PMID: 39130376 PMCID: PMC11310129 DOI: 10.3389/fnins.2024.1414145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 07/11/2024] [Indexed: 08/13/2024] Open
Abstract
Tauopathy is known to be a major pathognomonic finding in important neurodegenerative diseases such as progressive supranuclear palsy (PSP) and corticobasal degeneration. However, the mechanism by which tauopathy is triggered remains to be elucidated. We previously identified the point mutation c.11596C > G, p.Pro3866Ala in the Bassoon gene (BSN) in a Japanese family with PSP-like syndrome. We showed that mutated BSN may have been involved in its own insolubilization and tau accumulation. Furthermore, BSN mutations have also been related to various neurological diseases. In order to further investigate the pathophysiology of BSN mutation in detail, it is essential to study it in mouse models. We generated a mouse model with the mouse Bassoon p.P3882A mutation, which corresponds to the human BSN p.P3866A mutation, knock-in (KI) and we performed systematic behavioral and histological analyses. Behavioral analyses revealed impaired working memory in a Y-maze test at 3 months of age and decreased locomotor activity in the home cage at 3 and 12 months of age in KI mice compared to those in wild-type mice. Although no obvious structural abnormalities were observed at 3 months of age, immunohistochemical studies showed elevation of Bsn immunoreactivity in the hippocampus and neuronal loss without tau accumulation in the substantia nigra at 12 months of age in KI mice. Although our mice model did not show progressive cognitive dysfunction and locomotor disorder like PSP-like syndrome, dopaminergic neuronal loss was observed in the substantia nigra in 12-month-old KI mice. It is possible that BSN mutation may result in dopaminergic neuronal loss without locomotor symptoms due to the early disease stage. Thus, further clinical course can induce cognitive dysfunction and locomotor symptoms.
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Affiliation(s)
- Daiki Tanaka
- Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiroaki Yaguchi
- Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kaichi Yoshizaki
- Department of Disease Model, Aichi Developmental Disability Center, Kasugai, Japan
- Integrated Analysis of Bioresource and Health Care, Future Medical Sciences, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Akihiko Kudo
- Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Fumiaki Mori
- Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Taichi Nomura
- Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Jing Pan
- Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yasuo Miki
- Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hidehisa Takahashi
- Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Taichi Hara
- Laboratory of Food and Life Science, Faculty of Human Sciences, Waseda University, Tokyo, Japan
| | - Koichi Wakabayashi
- Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Ichiro Yabe
- Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Bransom L, Bassett AP, Zhou M, Cimino JX, Mailman RB, Yang Y. Dopamine D 1 Receptor Agonists Rescue Age-related Decline in Temporal Order Memory. Neuroscience 2024; 551:177-184. [PMID: 38823551 PMCID: PMC11246218 DOI: 10.1016/j.neuroscience.2024.05.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/08/2024] [Accepted: 05/27/2024] [Indexed: 06/03/2024]
Abstract
Dopamine D1 receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D1 agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D1-mediated cAMP synthesis. Conversely, at D1-mediated β-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D1 agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index.
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Affiliation(s)
- Luke Bransom
- Department of Pharmacology, Penn State University College of Medicine, Hershey PA 17033, United States
| | - Ava P Bassett
- Department of Pharmacology, Penn State University College of Medicine, Hershey PA 17033, United States
| | - Mi Zhou
- Department of Pharmacology, Penn State University College of Medicine, Hershey PA 17033, United States; Department of Neurology, Penn State University College of Medicine, Hershey, PA 17033, United States
| | - Jack X Cimino
- Department of Pharmacology, Penn State University College of Medicine, Hershey PA 17033, United States
| | - Richard B Mailman
- Department of Pharmacology, Penn State University College of Medicine, Hershey PA 17033, United States; Department of Neurology, Penn State University College of Medicine, Hershey, PA 17033, United States
| | - Yang Yang
- Department of Pharmacology, Penn State University College of Medicine, Hershey PA 17033, United States.
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Ohtake M, Abe K, Hasegawa M, Itokazu T, Selvakumar V, Matunis A, Stacy E, Froebrich E, Huynh N, Lee H, Kambe Y, Yamamoto T, Sato TK, Sato TR. Encoding of self-initiated actions in axon terminals of the mesocortical pathway. NEUROPHOTONICS 2024; 11:033408. [PMID: 38726349 PMCID: PMC11080647 DOI: 10.1117/1.nph.11.3.033408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/01/2024] [Accepted: 03/05/2024] [Indexed: 05/12/2024]
Abstract
Significance The initiation of goal-directed actions is a complex process involving the medial prefrontal cortex and dopaminergic inputs through the mesocortical pathway. However, it is unclear what information the mesocortical pathway conveys and how it impacts action initiation. In this study, we unveiled the indispensable role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. Aim To investigate the role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. Approach We designed a lever-press task in which mice internally determine the timing of the press, receiving a larger reward for longer waiting periods. Results Our study revealed that self-initiated actions depend on dopaminergic signaling mediated by D2 receptors, whereas sensory-triggered lever-press actions do not involve D2 signaling. Microprism-mediated two-photon calcium imaging further demonstrated ramping activity in mesocortical axon terminals approximately 0.5 s before the self-initiated lever press. Remarkably, the ramping patterns remained consistent whether the mice responded to cues immediately for a smaller reward or held their response for a larger reward. Conclusions We conclude that mesocortical dopamine axon terminals encode the timing of self-initiated actions, shedding light on a crucial aspect of the intricate neural mechanisms governing goal-directed behavior.
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Affiliation(s)
- Makoto Ohtake
- Medical University of South Carolina, Department of Neuroscience, Charleston, South Carolina, United States
- Yokohama City University, Department of Neurosurgery, Yokohama, Japan
| | - Kenta Abe
- Medical University of South Carolina, Department of Neuroscience, Charleston, South Carolina, United States
| | - Masashi Hasegawa
- Rutgers, The State University of New Jersey, Robert Wood Johnson Medical School, Center for Advanced Biotechnology and Medicine, Department of Neuroscience and Cell Biology, Piscataway, New Jersey, United States
| | - Takahide Itokazu
- Osaka University, Department of Neuro-Medical Science, Osaka, Japan
| | - Vihashini Selvakumar
- Medical University of South Carolina, Department of Neuroscience, Charleston, South Carolina, United States
| | - Ashley Matunis
- Medical University of South Carolina, Department of Neuroscience, Charleston, South Carolina, United States
- College of Charleston, Department of Biology, Charleston, South Carolina, United States
| | - Emma Stacy
- Medical University of South Carolina, Department of Neuroscience, Charleston, South Carolina, United States
- College of Charleston, Department of Biology, Charleston, South Carolina, United States
| | - Emily Froebrich
- Medical University of South Carolina, Department of Neuroscience, Charleston, South Carolina, United States
- College of Charleston, Department of Biology, Charleston, South Carolina, United States
| | - Nathan Huynh
- Kagoshima University, Department of Pharmacology, Kagoshima, Japan
| | - Haesuk Lee
- Kagoshima University, Department of Pharmacology, Kagoshima, Japan
| | - Yuki Kambe
- Kagoshima University, Department of Pharmacology, Kagoshima, Japan
| | - Tetsuya Yamamoto
- Yokohama City University, Department of Neurosurgery, Yokohama, Japan
| | - Tatsuo K. Sato
- Kagoshima University, Department of Pharmacology, Kagoshima, Japan
- FOREST, Japan Science and Technology Agency, Saitama, Japan
| | - Takashi R. Sato
- Medical University of South Carolina, Department of Neuroscience, Charleston, South Carolina, United States
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Maximiliano JE, Ares I, Martínez M, Lopez-Torres B, Martínez-Larrañaga MR, Anadón A, Martínez MA. Dopaminergic and serotoninergic systems as preferential targets of the pyrethroid tefluthrin exposure in the rat brain. ENVIRONMENTAL RESEARCH 2024; 247:118239. [PMID: 38244974 DOI: 10.1016/j.envres.2024.118239] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 01/22/2024]
Abstract
The monoaminergic systems dopamine (DA) and serotonin (5-HT) play important roles in neuromodulation, such as motor control, cognitive, affective, and neuroendocrine functions. In the present research study, we addressed the hypothesis that exposure to Type I pyrethroid tefluthrin may specifically target the dopaminergic and serotoninergic systems. Tefluthrin could modify brain monoamine neurotransmitters, DA and 5-HT levels as well as dopaminergic and serotoninergic signaling pathways. Adult male Wistar rats were treated with tefluthrin [2.2, 4.4 and 5.5 mg/kg bw, equivalent to 1/10, 1/5 and 1/4 of the acute oral rat lethal dose 50 (LD50) value] by oral gavage, six days. After last dose of tefluthrin, DA and 5-HT and metabolites levels were determined in brain regions (striatum, hippocampus, prefrontal cortex and hypothalamus). Tefluthrin induced a decrease of DA, 5-HT and metabolites contents, in a brain regional- and dose-related manner. The major decreases in DA and 5-HT contents were observed in prefrontal cortex tissue. Here, we studied that in vivo exposure to tefluthrin may alter DA and 5-HT neurotransmission in prefrontal cortex. Transcripts related to (i) dopaminergic [dopamine transporter 1 (Dat1), tyrosine hydroxylase (TH), dopamine receptors (Drd1, Drd2)], (ii) serotoninergic [serotonin transporter (SERT), tryptophan hydroxylase 2 (TPH2), serotonin receptors (5-HT1A, 5-HT2A)] and (iii) DA and 5-HT degradation [monoamine oxidases (MAOA, MAOB)] signaling pathways were investigated. Results showed that tefluthrin induced down-regulation of transcripts responsible for the synthesis and action of DA (TH, Drd1, Drd2) and 5-HT (SERT, TPH2). In contrast, tefluthrin treatment induced up-regulation of genes involved in DA transporter (Dat1), 5-HT receptors (5-HT1A, 5-HT2A) and monoamine oxidases (MAOA, MAOB). Given the integral roles of mitochondrial dysfunction and dopaminergic and serotoninergic alterations as hallmarks of neurodegenerative diseases, our data suggest that tefluthrin may be a candidate for pesticides contributing to neurodegenerative disorders pathogenesis by causing damage to the DA and 5-HT systems.
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Affiliation(s)
- Jorge-Enrique Maximiliano
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Irma Ares
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
| | - Marta Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
| | - Bernardo Lopez-Torres
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - María-Rosa Martínez-Larrañaga
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Arturo Anadón
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - María-Aránzazu Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
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11
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Elmers J, Colzato LS, Ziemssen F, Ziemssen T, Beste C. Optical coherence tomography as a potential surrogate marker of dopaminergic modulation across the life span. Ageing Res Rev 2024; 96:102280. [PMID: 38518921 DOI: 10.1016/j.arr.2024.102280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 02/02/2024] [Accepted: 03/18/2024] [Indexed: 03/24/2024]
Abstract
The retina has been considered a "window to the brain" and shares similar innervation by the dopaminergic system with the cortex in terms of an unequal distribution of D1 and D2 receptors. Here, we provide a comprehensive overview that Optical Coherence Tomography (OCT), a non-invasive imaging technique, which provides an "in vivo" representation of the retina, shows promise to be used as a surrogate marker of dopaminergic neuromodulation in cognition. Overall, most evidence supports reduced retinal thickness in individuals with dopaminergic dysregulation (e.g., patients with Parkinson's Disease, non-demented older adults) and with poor cognitive functioning. By using the theoretical framework of metacontrol, we derive hypotheses that retinal thinning associated to decreased dopamine (DA) levels affecting D1 families, might lead to a decrease in the signal-to-noise ratio (SNR) affecting cognitive persistence (depending on D1-modulated DA activity) but not cognitive flexibility (depending on D2-modulated DA activity). We argue that the use of OCT parameters might not only be an insightful for cognitive neuroscience research, but also a potentially effective tool for individualized medicine with a focus on cognition. As our society progressively ages in the forthcoming years and decades, the preservation of cognitive abilities and promoting healthy aging will hold of crucial significance. OCT has the potential to function as a swift, non-invasive, and economical method for promptly recognizing individuals with a heightened vulnerability to cognitive deterioration throughout all stages of life.
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Affiliation(s)
- Julia Elmers
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany; Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Lorenza S Colzato
- Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China
| | - Focke Ziemssen
- Ophthalmological Clinic, University Clinic Leipzig, Germany
| | - Tjalf Ziemssen
- Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Christian Beste
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany; Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China.
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12
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Nesbit MO, Ahn S, Zou H, Floresco SB, Phillips AG. Potentiation of prefrontal cortex dopamine function by the novel cognitive enhancer d-govadine. Neuropharmacology 2024; 246:109849. [PMID: 38244888 DOI: 10.1016/j.neuropharm.2024.109849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/13/2023] [Accepted: 01/16/2024] [Indexed: 01/22/2024]
Abstract
Cognitive impairment is a debilitating feature of psychiatric disorders including schizophrenia, mood disorders and substance use disorders for which there is a substantial lack of effective therapies. d-Govadine (d-GOV) is a tetrahydroprotoberberine recently shown to significantly enhance working memory and behavioural flexibility in several prefrontal cortex (PFC)-dependent rodent tasks. d-GOV potentiates dopamine (DA) efflux in the mPFC and not the nucleus accumbens, a unique pharmacology that sets it apart from many dopaminergic drugs and likely contributes to its effects on cognitive function. However, specific mechanisms involved in the preferential effects of d-GOV on mPFC DA function remain to be determined. The present study employs brain dialysis in male rats to deliver d-GOV into the mPFC or ventral tegmental area (VTA), while simultaneously sampling DA and norepinephrine (NE) efflux in the mPFC. Intra-PFC delivery or systemic administration of d-GOV preferentially potentiated medial prefrontal DA vs NE efflux. This differential effect of d-GOV on the primary catecholamines known to affect mPFC function further underscores its specificity for the mPFC DA system. Importantly, the potentiating effect of d-GOV on mPFC DA was disrupted when glutamatergic transmission was blocked in either the mPFC or the VTA. We hypothesize that d-GOV acts in the mPFC to engage the mesocortical feedback loop through which prefrontal glutamatergic projections activate a population of VTA DA neurons that specifically project back to the PFC. The activation of a PFC-VTA feedback loop to elevate PFC DA efflux without affecting mesolimbic DA release represents a novel approach to developing pro-cognitive drugs.
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Affiliation(s)
- Maya O Nesbit
- Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Soyon Ahn
- Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Haiyan Zou
- Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Stan B Floresco
- Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Anthony G Phillips
- Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
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13
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Rajagopal L, Huang M, Mahjour S, Ryan C, Elzokaky A, Svensson KA, Meltzer HY. The dopamine D1 receptor positive allosteric modulator, DETQ, improves cognition and social interaction in aged mice and enhances cortical and hippocampal acetylcholine efflux. Behav Brain Res 2024; 459:114766. [PMID: 38048913 DOI: 10.1016/j.bbr.2023.114766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 11/06/2023] [Accepted: 11/15/2023] [Indexed: 12/06/2023]
Abstract
Dopamine (DA) D1 and D2 receptors (Rs) are critical for cognitive functioning. D1 positive allosteric modulators (D1PAMs) activate D1Rs without desensitization or an inverted U-shaped dose response curve. DETQ, [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one] is highly selective for the human D1Rs as shown in humanized D1R knock-in (hD1Ki) mice. Here, we have ascertained the efficacy of DETQ in aged [13-23-month-old (mo)] hD1Ki mice and their corresponding age-matched wild-type (WT; C57BL/6NTac) controls. We found that in aged mice, DETQ, given acutely, subchronically, and chronically, rescued both novel object recognition memory and social behaviors, using novel object recognition (NOR) and social interaction (SI) tasks, respectively without any adverse effect on body weight or mortality. We have also shown, using in vivo microdialysis, a significant decrease in basal DA and norepinephrine, increase in glutamate (Glu) and gamma-amino butyric acid (GABA) efflux with no significant changes in acetylcholine (ACh) levels in aged vs young mice. In young and aged hD1Ki mice, DETQ, acutely and subchronically increased ACh in the medial prefrontal cortex and hippocampal regions in aged hD1Ki mice without affecting Glu. These results suggest that the D1PAM mechanism is of interest as potential treatment for cognitive and social behavioral deficits in neuropsychiatric disorders including but not restricted to neurodegenerative disorders, such as Parkinson's disease.
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Affiliation(s)
- Lakshmi Rajagopal
- Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Mei Huang
- Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Sanaz Mahjour
- Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Chelsea Ryan
- Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Ahmad Elzokaky
- Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Kjell A Svensson
- Neuroscience Discovery, Eli Lilly & Company, Indianapolis, IN, USA
| | - H Y Meltzer
- Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
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14
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Iravani MM, Shoaib M. Executive dysfunction and cognitive decline, a non-motor symptom of Parkinson's disease captured in animal models. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 174:231-255. [PMID: 38341231 DOI: 10.1016/bs.irn.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2024]
Abstract
The non-motor symptoms of Parkinson's disease (PD) have gained increasing attention in recent years due to their significant impact on patients' quality of life. Among these non-motor symptoms, cognitive dysfunction has emerged as an area of particular interest where the clinical aspects are covered in Chapter 2 of this volume. This chapter explores the rationale for investigating the underlying neurobiology of cognitive dysfunction by utilising translational animal models of PD, from rodents to non-human primates. The objective of this chapter is to review the various animal models of cognition that have explored the dysfunction in animal models of Parkinson's disease. Some of the more advanced pharmacological studies aimed at restoring these cognitive deficits are reviewed, although this chapter highlights the lack of systematic approaches in dealing with this non-motor symptom at the pre-clinical stages.
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15
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Schachar RJ. Fifty years of executive control research in attention-deficit/hyperactivity disorder:What we have learned and still need to know. Neurosci Biobehav Rev 2023; 155:105461. [PMID: 37949153 DOI: 10.1016/j.neubiorev.2023.105461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/12/2023]
Abstract
For 50 years, attention-deficit/hyperactivity disorder (ADHD) has been considered a disorder of executive control (EC), the higher-order, cognitive skills that support self-regulation, goal attainment and what we generally call "attention." This review surveys our current understanding of the nature of EC as it pertains to ADHD and considers the evidence in support of eight hypotheses that can be derived from the EC theory of ADHD. This paper provides a resource for practitioners to aid in clinical decision-making. To support theory building, I draw a parallel between the EC theory of ADHD and the common gene-common variant model of complex traits such as ADHD. The conclusion offers strategies for advancing collaborative research.
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Affiliation(s)
- Russell J Schachar
- Department of Psychiatry, The Hospital for Sick Children and University of Toronto, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G1X8, Canada.
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16
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Seo JP, Ryu HJ. Aging of reward dopamine tracts in the human brain: A diffusion tensor imaging study. Medicine (Baltimore) 2023; 102:e36112. [PMID: 37986323 PMCID: PMC10659658 DOI: 10.1097/md.0000000000036112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 10/09/2023] [Accepted: 10/24/2023] [Indexed: 11/22/2023] Open
Abstract
The mesocortical tract (MCT) and mesolimbic tract (MLT) are reward dopaminergic tracts that have been shown to play a role in regulating reward stimuli, including both incentive salience and social stimuli. In the current study, we examined aging of the MCT and MLT in normal human participants to explain human brain structures using diffusion tensor tractography (DTT). Sixty-four healthy participants were recruited for this study and allocated to 3 groups based on participants' age. Diffusion tensor imaging was performed, and MCTs and MLTs were reconstructed using the probabilistic tractography method. A significant negative correlation was observed between age and fractional anisotropy and tract volume of the MCT and MLT, whereas a positive correlation was observed between age and mean diffusivity. The mean fractional anisotropy value of the MCT was significantly lower in the old group than in the young and middle-aged groups (P < .05). The mean diffusivity values of the MCT and MLT were significantly higher in the old group than in the young and middle-aged groups (P < .05). The mean tract volume values of the MCT and MLT were significantly lower in the old group than in the young group (P < .05). We found that degenerative changes in the MCT and MLT began in participants in the 20s-30s, progressed steadily throughout life, and accelerated in the 60s.
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Affiliation(s)
- Jeong Pyo Seo
- Department of Physical Therapy, College of Health and Welfare Sciences, Dankook University, Cheonan, Republic of Korea
| | - Heun Jae Ryu
- Department of Public Health Sciences, Graduate School, Dankook University, Cheonan, Republic of Korea
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17
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Alaee E, Pachenari N, Khani F, Semnanian S, Shojaei A, Azizi H. Enhancement of neuronal excitability in the medial prefrontal cortex following prenatal morphine exposure. Brain Res Bull 2023; 204:110803. [PMID: 37913849 DOI: 10.1016/j.brainresbull.2023.110803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/26/2023] [Accepted: 10/28/2023] [Indexed: 11/03/2023]
Abstract
The clinical use and abuse of opioids during human pregnancy have been widely reported. Several studies have demonstrated that opioids cross the placenta in rats during late gestation, and prenatal morphine exposure has been shown to have negative outcomes in cognitive function. The medial prefrontal cortex (mPFC) is believed to play a crucial role in cognitive processes, motivation, and emotion, integrating neural information from several brain areas and sending converted information to other structures. Dysfunctions in this area have been observed in numerous psychiatric and neurological disorders, including addiction. This current study aimed to compare the electrophysiological properties of mPFC neurons in rat offspring prenatally exposed to morphine. Pregnant rats were injected with morphine or saline twice a day from gestational days 11-18. Whole-cell patch-clamp recordings were performed in male offspring on postnatal days 14-18. All recordings were obtained in current-clamp configuration from mPFC pyramidal neurons to assess their electrophysiological properties. The results revealed that prenatal exposure to morphine shifted the resting membrane potential (RMP) to less negative voltages and increased input resistance and duration of action potentials. However, the amplitude, rise slope, and afterhyperpolarization (AHP) amplitude of the first elicited action potentials were significantly decreased in rats prenatally exposed to morphine. Moreover, the sag voltage ratio was significantly decreased in the prenatal morphine group. Our results suggest that the changes observed in the electrophysiological properties of mPFC neurons indicate an elevation in neuronal excitability following prenatal exposure to morphine.
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Affiliation(s)
- Elham Alaee
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Narges Pachenari
- School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
| | - Fatemeh Khani
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeed Semnanian
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Institute for Brain Sciences and Cognition, Tarbiat Modares University, Tehran, Iran
| | - Amir Shojaei
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Institute for Brain Sciences and Cognition, Tarbiat Modares University, Tehran, Iran
| | - Hossein Azizi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Institute for Brain Sciences and Cognition, Tarbiat Modares University, Tehran, Iran.
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18
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Cimino JX, Zhou M, Waxmonsky J, Mailman RB, Yang Y. Characterization of behavioral changes in T-maze alternation from dopamine D 1 agonists with different receptor coupling mechanisms. Psychopharmacology (Berl) 2023; 240:2187-2199. [PMID: 37578525 PMCID: PMC10693963 DOI: 10.1007/s00213-023-06440-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/26/2023] [Indexed: 08/15/2023]
Abstract
RATIONALE Dopamine D1 receptor agonists have been shown to improve working memory, but often have a non-monotonic (inverted-U) dose-response curve. One hypothesis is that this may reflect dose-dependent differential engagement of D1 signaling pathways, a mechanism termed functional selectivity or signaling bias. OBJECTIVES AND METHODS To test this hypothesis, we compared two D1 ligands with different signaling biases in a rodent T-maze alternation task. Both tested ligands (2-methyldihydrexidine and CY208243) have high intrinsic activity at cAMP signaling, but the former also has markedly higher intrinsic activity at D1-mediated recruitment of β-arrestin. The spatial working memory was assessed via the alternation behavior in the T-maze where the alternate choice rate quantified the quality of the memory and the duration prior to making a choice represented the decision latency. RESULTS Both D1 drugs changed the alternate rate and the choice latency in a dose-dependent manner, albeit with important differences. 2-Methyldihydrexidine was somewhat less potent but caused a more homogeneous improvement than CY208243 in spatial working memory. The maximum changes in the alternate rate and the choice latency tended to occur at different doses for both drugs. CONCLUSIONS These data suggest that D1 signaling bias in these two pathways (cAMP vs β-arrestin) has complex effects on cognitive processes as assessed by T-maze alternation. Understanding these mechanisms should allow the identification or discovery of D1 agonists that can provide superior cognitive enhancement.
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Affiliation(s)
- Jack X Cimino
- Neuroscience Program, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Mi Zhou
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, 17033, USA
- Department of Neurology, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - James Waxmonsky
- Department of Psychiatry and Behavioral Health, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Richard B Mailman
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, 17033, USA
- Department of Neurology, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Yang Yang
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, 17033, USA.
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Gungor Aydin A, Adiguzel E. The mesocortical dopaminergic system cannot explain hyperactivity in an animal model of attention deficit hyperactivity disorder (ADHD)- Spontaneously hypertensive rats (SHR). Lab Anim Res 2023; 39:20. [PMID: 37710339 PMCID: PMC10500870 DOI: 10.1186/s42826-023-00172-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/24/2023] [Accepted: 09/02/2023] [Indexed: 09/16/2023] Open
Abstract
BACKGROUND Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent neuropsychiatric disorders with morphological brain abnormalities. There is a growing body of evidence that abnormalities in the dopaminergic system may account for ADHD pathogenesis. However, it is not clear whether the dopaminergic system is hyper or hypoactive. To determine whether the DA neurons and/or axons deficiency might be the cause of the postulated dopaminergic hypofunction in spontaneously hypertensive rats (SHR, animal model of ADHD), this study examined the dopaminergic neurons and fibers in the brain tissues of SHRs and Wistar Kyoto rats (WKY, control animals). Here, we performed immunohistochemical tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) staining on brain sections collected on juveniles from SHR and WKY. Moreover, behavioral testing to examine the hyperactivity in the open field area was also elucidated. RESULTS The mesocortical dopaminergic system appears to be normal in juvenile SHR, as suggested by (i) no alteration in the area density of TH-immunoreactive (TH-ir) dopaminergic neurons in the ventral tegmental area (VTA), (ii) no alterations in the volume density of TH-ir fibers in layer I of the prelimbic (PrL) subregion of medial PFC (mPFC), (iii) no alteration in the percentage of TH-ir dopaminergic fibers in layer I of the PrL subregion of mPFC as revealed by TH and/or DBH immunoreactivity. Furthermore, the SHR showed increased locomotor activity than WKY in the open field test. CONCLUSIONS The demonstration of no alteration in mesocortical dopaminergic neurons and fiber in SHR raises some concern about the position of SHR as an animal model of the inattentive subtype of ADHD. However, these results strengthen this strain as an animal model of hyperactive/impulsive subtype ADHD for future studies that may elucidate the underlying mechanism mediating hyperactivity and test various treatment strategies.
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Affiliation(s)
- Aysegul Gungor Aydin
- Department of Psychology, Rutgers University-New Brunswick, Piscataway, NJ, 08854, USA.
| | - Esat Adiguzel
- Department of Anatomy, Faculty of Medicine, Pamukkale University, 20070, Denizli, Turkey
- Department of Neuroscience, Institute of Health Sciences, Pamukkale University, 20070, Denizli, Turkey
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20
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Sagheddu C, Devoto P, Aroni S, Saba P, Pistis M, Gessa GL. Combined α 2- and D 2-receptor blockade activates noradrenergic and dopaminergic neurons, but extracellular dopamine in the prefrontal cortex is determined by uptake and release from noradrenergic terminals. Front Pharmacol 2023; 14:1238115. [PMID: 37680715 PMCID: PMC10482411 DOI: 10.3389/fphar.2023.1238115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 08/10/2023] [Indexed: 09/09/2023] Open
Abstract
Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α2-adrenoceptor antagonists rescue dopamine deficit and improve the antipsychotic efficacy of D2-receptor antagonists. In anesthetized male rats, we investigated how the blockade of α2- and D2-receptors by atipamezole and raclopride, respectively, modified the firing of noradrenergic neurons in the locus coeruleus (LC) and dopaminergic neurons in the ventral tegmental area (VTA). In freely moving rats, we studied how atipamezole and raclopride modified extracellular noradrenaline, dopamine, and DOPAC levels in the medial prefrontal cortex (mPFC) through microdialysis. When administered alone, atipamezole activated LC noradrenaline but not VTA dopamine cell firing. Combined with raclopride, atipamezole activated dopamine cell firing above the level produced by raclopride. Atipamezole increased extracellular dopamine to the same level, whether administered alone or combined with raclopride. In the presence of the noradrenaline transporter (NET) inhibitor, atipamezole combined with raclopride increased extracellular dopamine beyond the level produced by either compound administered alone. The results suggest that a) the D2-autoreceptor blockade is required for LC noradrenaline to activate VTA cell firing; b) the level of dopamine released from dopaminergic terminals is determined by NET; c) the elevation of extracellular dopamine levels in the mPFC is the resultant of dopamine uptake and release from noradrenergic terminals, independent of dopaminergic cell firing and release; and d) LC noradrenergic neurons are an important target for treatments to improve the prefrontal deficit of dopamine in neuropsychiatric pathologies.
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Affiliation(s)
- Claudia Sagheddu
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Paola Devoto
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
- The Guy Everett Laboratory, University of Cagliari, Cagliari, Italy
| | - Sonia Aroni
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Pierluigi Saba
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
- The Guy Everett Laboratory, University of Cagliari, Cagliari, Italy
| | - Marco Pistis
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
- Neuroscience Institute of CNR, Cagliari, Italy
- Unit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy
| | - Gian Luigi Gessa
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
- The Guy Everett Laboratory, University of Cagliari, Cagliari, Italy
- Neuroscience Institute of CNR, Cagliari, Italy
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Yinka OS, Olubunmi OP, Zabdiel AA, Oladele OJ, Taiye AS, Ayodele A, Adetutu FO, Afees OJ, Kayode AA. Peroral Exposure to Cannabis Sativa Ethanol Extract Caused Neuronal Degeneration and Astrogliosis in Wistar Rats' Prefrontal Cortex. Ann Neurosci 2023; 30:84-95. [PMID: 37706104 PMCID: PMC10496793 DOI: 10.1177/09727531221120988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 07/25/2022] [Indexed: 09/15/2023] Open
Abstract
Background Despite widespread concerns about its possible side effects, notably on the prefrontal cortex (PFC), which mediates cognitive processes, the use of Cannabis sativa as a medicinal and recreational drug is expanding exponentially. This study evaluated possible behavioral alterations, neurotransmitter levels, histological, and immunohistochemical changes in the PFC of Wistar rats exposed to Cannabis sativa. Purpose To evaluate the effect of graded doses of Cannabis sativa on the PFC using behavioural, histological, and immunohistochemical approaches. Methods Twenty-eight juvenile male Wistar rats weighing between 70 g and 100 g were procured and assigned into groups A-D (n = 7 each). Group A served as control which received distilled water only as a placebo; rats in groups B, C, and D which were the treatment groups were orally exposed to graded doses of Cannabis sativa (10 mg/kg, 50 mg/kg, and 100 mg/kg, respectively). Rats in all experimental groups were exposed to Cannabis sativa for 21 days, followed by behavioral tests using the open field test for locomotor, anxiety, and exploratory activities, while the Y-maze test was for spatial memory assessment. Rats for biochemical analysis were cervically dislocated and rats for tissue processing were intracardially perfused following neurobehavioral tests. Sequel to sacrifice, brain tissues were excised and prefrontal cortices were obtained for the neurotransmitter (glutamate, acetylcholine, and dopamine) and enzymatic assay (Cytochrome C oxidase (CcO) and Glucose 6- Phosphate Dehydrogenase-G-6-PDH). Brain tissues were fixed in 10% Neutral Buffered Formalin (NBF) for histological demonstration of the PFC cytoarchitecture using H&E and glial fibrillary acidic protein (GFAP) for astrocyte evaluation. Results Glutamate and dopamine levels were significantly increased (F = 24.44, P = .0132) in groups D, and B, C, and D, respectively, compared to control; likewise, the activities of CcO and G-6-PDH were also significantly elevated (F = 96.28, P = .0001) (F = 167.5, P = .0001) in groups C and D compared to the control. Cannabis sativa impaired locomotor activity and spatial memory in B and D and D, respectively. All Cannabis sativa exposed groups demonstrated evidence of neurodegeneration in the exposed groups; GFAP immunoexpression was evident in all groups with a marked increase in group D. Conclusion Cannabis sativa altered neurotransmitter levels, energy metabolism, locomotor, and exploratory activity, and spatial working memory, with neuronal degeneration as well as reactive astrogliosis in the PFC.
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Affiliation(s)
- Olatunji Sunday Yinka
- Department of Anatomy, School of Basic Medical Sciences, Benjamin Carson (Snr.) College of Medical and Health Sciences, Ilishan-Remo, Ogun State Nigeria
- Anatomy Department, Adventist School of Medicine of East-Central Africa, Adventist University of Central Africa, Kigali, Rwanda
| | - Ogunnaike Philip Olubunmi
- Department of Anatomy, School of Basic Medical Sciences, Benjamin Carson (Snr.) College of Medical and Health Sciences, Ilishan-Remo, Ogun State Nigeria
| | - Abijo Ayodeji Zabdiel
- Department of Anatomy, School of Basic Medical Sciences, Benjamin Carson (Snr.) College of Medical and Health Sciences, Ilishan-Remo, Ogun State Nigeria
| | - Owolabi Joshua Oladele
- Department of Anatomy, School of Basic Medical Sciences, Benjamin Carson (Snr.) College of Medical and Health Sciences, Ilishan-Remo, Ogun State Nigeria
- Anatomy Department, Division of Basic Medical Sciences, University of Global Health Equity, Kigali, Rwanda
| | - Adelodun Stephen Taiye
- Department of Anatomy, School of Basic Medical Sciences, Benjamin Carson (Snr.) College of Medical and Health Sciences, Ilishan-Remo, Ogun State Nigeria
| | - Adeoye Ayodele
- Department of Education, School of Education and Humanities, Babcock University, Ilisan-Remo, Ogun State, Nigeria
| | - Fasesan Oluwatoyin Adetutu
- Department of Psychiatry, Ben Carson School of Medicine, Babcock University, Ilisan-Remo, Ogun State, Nigeria
| | - Olanrewaju John Afees
- Department of Anatomy, School of Basic Medical Sciences, Benjamin Carson (Snr.) College of Medical and Health Sciences, Ilishan-Remo, Ogun State Nigeria
| | - Adegbite Ademola Kayode
- Department of Anatomy, School of Basic Medical Sciences, Benjamin Carson (Snr.) College of Medical and Health Sciences, Ilishan-Remo, Ogun State Nigeria
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Arnsten AFT, Joyce MKP, Roberts AC. The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion. Neurosci Biobehav Rev 2023; 145:105000. [PMID: 36529312 PMCID: PMC9898199 DOI: 10.1016/j.neubiorev.2022.105000] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/08/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022]
Abstract
ARNSTEN, A.F.T., M.K.P. Joyce and A.C. Roberts. The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion. NEUROSCI BIOBEHAV REV XXX-XXX, 2022. The symptoms of major-depressive-disorder include psychic pain and anhedonia, i.e. seeing the world through an "aversive lens". The neurobiology underlying this shift in worldview is emerging. Here these data are reviewed, focusing on how activation of subgenual cingulate (BA25) induces an "aversive lens", and how higher prefrontal cortical (PFC) areas (BA46/10/32) provide top-down regulation of BA25 but are weakened by excessive dopamine and norepinephrine release during stress exposure, and dendritic spine loss with chronic stress exposure. These changes may generate an attractor state, which maintains the brain under the control of BA25, requiring medication or neuromodulatory treatments to return connectivity to a more flexible state. In line with this hypothesis, effective anti-depressant treatments reduce the activity of BA25 and restore top-down regulation by higher circuits, e.g. as seen with SSRI medications, ketamine, deep brain stimulation of BA25, or rTMS to strengthen dorsolateral PFC. This research has special relevance in an era of chronic stress caused by the COVID19 pandemic, political unrest and threat of climate change.
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Affiliation(s)
- Amy F T Arnsten
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
| | - Mary Kate P Joyce
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
| | - Angela C Roberts
- Department Physiology, Development and Neuroscience, and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3DY, UK.
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23
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Fox HC, Milivojevic V, Sinha R. Therapeutics for Substance-Using Women: The Need to Elucidate Sex-Specific Targets for Better-Tailored Treatments. Handb Exp Pharmacol 2023; 282:127-161. [PMID: 37592081 DOI: 10.1007/164_2023_687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/19/2023]
Abstract
In the last decade, alcohol consumption in the US has risen by 84% in women compared with 35% in men. Furthermore, research has shown that sex- and gender-related differences may disadvantage women in terms of developing a range of psychological, cognitive, and medical problems considerably earlier in their drinking history than men, and despite consuming a similar quantity of substances. While this "telescoping" process has been acknowledged in the literature, a concomitant understanding of the underlying biobehavioral mechanisms, and an increase in the development of specific treatments tailored to women, has not occurred. In the current chapter we focus on understanding why the need for personalized, sex-specific medications is imperative, and highlight some of the potential sex-specific gonadal and stress-related adaptations underpinning the accelerated progress from controlled to compulsive drug and alcohol seeking in women. We additionally discuss the efficacy of these mechanisms as novel targets for medications development, using exogenous progesterone and guanfacine as examples. Finally, we assess some of the challenges faced and progress made in terms of developing innovative medications in women. We suggest that agents such as exogenous progesterone and adrenergic medications, such as guanfacine, may provide some efficacy in terms of attenuating stress-induced craving for several substances, as well as improving the ability to emotionally regulate in the face of stress, preferentially in women. However, to fully leverage the potential of these therapeutics in substance-using women, greater focus needs to the placed on reducing barriers to treatment and research by encouraging women into clinical trials.
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Affiliation(s)
- Helen C Fox
- Department of Psychiatry and Behavioral Health, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
| | - Verica Milivojevic
- The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Rajita Sinha
- The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
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Kamińska K, Lenda T, Konieczny J, Lorenc-Koci E. Behavioral and neurochemical interactions of the tricyclic antidepressant drug desipramine with L-DOPA in 6-OHDA-lesioned rats. Implications for motor and psychiatric functions in Parkinson's disease. Psychopharmacology (Berl) 2022; 239:3633-3656. [PMID: 36178508 PMCID: PMC9584871 DOI: 10.1007/s00213-022-06238-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 09/12/2022] [Indexed: 11/11/2022]
Abstract
RATIONALE The pharmacological effects of antidepressants in modulating noradrenergic transmission as compared to serotonergic transmission in a rat model of Parkinson's disease under chronic L-DOPA therapy are insufficiently explored. OBJECTIVES The aim of the present study was to investigate the effect of the tricyclic antidepressant desipramine administered chronically alone or jointly with L-DOPA, on motor behavior and monoamine metabolism in selected brain structures of rats with the unilateral 6-OHDA lesion. METHODS The antiparkinsonian activities of L-DOPA and desipramine were assessed behaviorally using a rotation test and biochemically based on changes in the tissue concentrations of noradrenaline, dopamine and serotonin and their metabolites, evaluated separately for the ipsi- and contralateral motor (striatum, substantia nigra) and limbic (prefrontal cortex, hippocampus) structures of rat brain by HPLC method. RESULTS Desipramine administered alone did not induce rotational behavior, but in combination with L-DOPA, it increased the number of contralateral rotations more strongly than L-DOPA alone. Both L-DOPA and desipramine + L-DOPA significantly increased DA levels in the ipsilateral striatum, substantia nigra, prefrontal cortex and the ipsi- and contralateral hippocampus. The combined treatment also significantly increased noradrenaline content in the ipsi- and contralateral striatum, while L-DOPA alone decreased serotonin level on both sides of the hippocampus. CONCLUSIONS The performed analysis of the level of monoamines and their metabolites in the selected brain structures suggests that co-modulation of noradrenergic and dopaminergic transmission in Parkinson's disease by the combined therapy with desipramine + L-DOPA may have some positive implications for motor and psychiatric functions but further research is needed to exclude potential negative effects.
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Affiliation(s)
- Kinga Kamińska
- Department of Neuro-Psychopharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna street 12, 31-343, Kraków, Poland
| | - Tomasz Lenda
- Department of Neuro-Psychopharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna street 12, 31-343, Kraków, Poland
| | - Jolanta Konieczny
- Department of Neuro-Psychopharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna street 12, 31-343, Kraków, Poland
| | - Elżbieta Lorenc-Koci
- Department of Neuro-Psychopharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna street 12, 31-343, Kraków, Poland.
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25
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Schacht JP, Yeongbin Im, Hoffman M, Voronin KE, Book SW, Anton RF. Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone. Neuropsychopharmacology 2022; 47:1953-1960. [PMID: 35523943 PMCID: PMC9073504 DOI: 10.1038/s41386-022-01335-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/08/2022] [Accepted: 04/25/2022] [Indexed: 11/09/2022]
Abstract
Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone's effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934.
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Affiliation(s)
- Joseph P Schacht
- Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA.
| | - Yeongbin Im
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Michaela Hoffman
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Konstantin E Voronin
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Sarah W Book
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Raymond F Anton
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
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Roberts SGB, Dunbar RIM, Roberts AI. Communicative roots of complex sociality and cognition: neuropsychological mechanisms underpinning the processing of social information. Philos Trans R Soc Lond B Biol Sci 2022; 377:20210295. [PMID: 35934969 PMCID: PMC9358321 DOI: 10.1098/rstb.2021.0295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 04/08/2022] [Indexed: 11/12/2022] Open
Abstract
Primate social bonds are described as being especially complex in their nature, and primates have unusually large brains for their body size compared to other mammals. Communication in primates has attracted considerable attention because of the important role it plays in social bonding. It has been proposed that differentiated social relationships are cognitively complex because primates need to continuously update their knowledge about different types of social bonds. Therefore, primates infer whether an opportunity for social interaction is rewarding (valuable to individual goals) based on their knowledge of the social relationships of the interactants. However, exposure to distraction and stress has detrimental effects on the dopaminergic system, suggesting that understanding social relationships as rewarding is affected in these conditions. This paper proposes that complex communication evolved to augment the capacity to form social relationships during stress through flexibly modifying intentionality in communication (audience checking, response waiting and elaboration). Intentional communication may upregulate dopamine dynamics to allow recognition that an interaction is rewarding during stress. By examining these associations between complexity of communication and stress, we provide new insights into the cognitive skills involved in forming social bonds in primates and the evolution of communication systems in both primates and humans. This article is part of the theme issue 'Cognition, communication and social bonds in primates'.
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Affiliation(s)
- Sam G. B. Roberts
- School of Psychology, Liverpool John Moores University, Liverpool L3 3AF, UK
| | - Robin I. M. Dunbar
- Department of Experimental Psychology, University of Oxford, Oxford OX2 6GG, UK
| | - Anna I. Roberts
- Institute of Human Biology and Evolution, Adam Mickiewicz University, Poznan, Poland
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27
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Gallo FT, Zanoni Saad MB, Silva A, Morici JF, Miranda M, Anderson MC, Weisstaub NV, Bekinschtein P. Dopamine Modulates Adaptive Forgetting in Medial Prefrontal Cortex. J Neurosci 2022; 42:6620-6636. [PMID: 35853718 PMCID: PMC9410750 DOI: 10.1523/jneurosci.0740-21.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/18/2022] [Accepted: 05/23/2022] [Indexed: 11/21/2022] Open
Abstract
Active forgetting occurs in many species, but how behavioral control mechanisms influence which memories are forgotten remains unknown. We previously found that when rats need to retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting relies on prefrontal control processes. Dopaminergic input to the prefrontal cortex is important for executive functions and cognitive flexibility. We found that, in a similar way, retrieval-induced forgetting of competing memories in male rats requires prefrontal dopamine signaling through D1 receptors. Blockade of medial prefrontal cortex D1 receptors as animals encountered a familiar object impaired active forgetting of competing object memories as measured on a later long-term memory test. Inactivation of the ventral tegmental area produced the same pattern of behavior, a pattern that could be reversed by concomitant activation of prefrontal D1 receptors. We observed a bidirectional modulation of retrieval-induced forgetting by agonists and antagonists of D1 receptors in the medial prefrontal cortex. These findings establish the essential role of prefrontal dopamine in the active forgetting of competing memories, contributing to the shaping of retention in response to the behavioral goals of an organism.SIGNIFICANCE STATEMENT Forgetting is a ubiquitous phenomenon that is actively promoted in many species. The very act of remembering some experiences can cause forgetting of others, in both humans and rats. This retrieval-induced forgetting process is thought to be driven by inhibitory control signals from the prefrontal cortex that target areas where the memories are stored. Here we started disentangling the neurochemical signals in the prefrontal cortex that are essential to retrieval-induced forgetting. We found that, in rats, the release of dopamine in this area, acting through D1 receptors, was essential to causing active forgetting of competing memories. Inhibition of D1 receptors impaired forgetting, while activation increased forgetting. These findings are important, because the mechanisms of active forgetting and their linkage to goal-directed behavior are only beginning to be understood.
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Affiliation(s)
- Francisco Tomás Gallo
- Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional, Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)-Fundación INECO-Universidad Favaloro, 1071 Ciudad Autónoma de Buenos Aires, Argentina
| | - María Belén Zanoni Saad
- Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional, Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)-Fundación INECO-Universidad Favaloro, 1071 Ciudad Autónoma de Buenos Aires, Argentina
| | - Azul Silva
- Grupo de Neurociencia de Sistemas, Instituto de Fisiología y Biofísica "Houssay" (IFIBIO "Houssay"), Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1121ABG Ciudad Autónoma de Buenos Aires, Argentina
| | - Juan Facundo Morici
- Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional, Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)-Fundación INECO-Universidad Favaloro, 1071 Ciudad Autónoma de Buenos Aires, Argentina
| | - Magdalena Miranda
- Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional, Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)-Fundación INECO-Universidad Favaloro, 1071 Ciudad Autónoma de Buenos Aires, Argentina
| | - Michael C Anderson
- MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge CB2 7EF, United Kingdom
- Behavioural and Clinical Neurosciences Unit, University of Cambridge, Cambridge CB2 3EB, United Kingdom
| | - Noelia V Weisstaub
- Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional, Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)-Fundación INECO-Universidad Favaloro, 1071 Ciudad Autónoma de Buenos Aires, Argentina
| | - Pedro Bekinschtein
- Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional, Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)-Fundación INECO-Universidad Favaloro, 1071 Ciudad Autónoma de Buenos Aires, Argentina
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Gregorio I, Mereu M, Contarini G, Bello L, Semplicini C, Burgio F, Russo L, Sut S, Dall'Acqua S, Braghetta P, Semenza C, Pegoraro E, Papaleo F, Bonaldo P, Cescon M. Collagen VI deficiency causes behavioral abnormalities and cortical dopaminergic dysfunction. Dis Model Mech 2022; 15:276265. [PMID: 35946603 PMCID: PMC9548377 DOI: 10.1242/dmm.049481] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 07/29/2022] [Indexed: 11/20/2022] Open
Abstract
Mutations of genes coding for Collagen VI (COL6) cause muscle diseases, including Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). Although more recently COL6 genetic variants were linked to brain pathologies, the impact of COL6 deficiency in brain function is still largely unknown. Here, a thorough behavioral characterization of COL6 null (Col6a1-/-) mice unexpectedly revealed that COL6 deficiency leads to a significant impairment in sensorimotor gating and memory/attention functions. In keeping with these behavioral abnormalities, Col6a1-/- mice displayed alterations in dopaminergic signalling, primarily in the prefrontal cortex (PFC). In vitro co-culture of SH-SY5Y neural cells with primary meningeal fibroblasts from wild-type and Col6a1-/- mice confirmed a direct link between COL6 ablation and defective dopaminergic activity, through a mechanism involving the inability of meningeal cells to sustain dopaminergic differentiation. Finally, patients affected by COL6-related myopathies were evaluated with an ad hoc neuropsychological protocol, revealing distinctive defects in attentional control abilities. Altogether, these findings point at a novel role for COL6 in the proper maintenance of dopamine circuitry function and its related neurobehavioral features in both mice and humans.
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Affiliation(s)
- Ilaria Gregorio
- Department of Molecular Medicine, University of Padova, 35131 Padova, Italy
| | - Maddalena Mereu
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Italy.,Genetics of Cognition Laboratory, Neuroscience Area, Istituto Italiano di Tecnologia, 16163, Genova, Italy
| | - Gabriella Contarini
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Italy.,Genetics of Cognition Laboratory, Neuroscience Area, Istituto Italiano di Tecnologia, 16163, Genova, Italy
| | - Luca Bello
- ERN Neuromuscular Center, Department of Neurosciences, University of Padova, 35129 Padova, Italy
| | - Claudio Semplicini
- ERN Neuromuscular Center, Department of Neurosciences, University of Padova, 35129 Padova, Italy
| | | | - Loris Russo
- Department of Molecular Medicine, University of Padova, 35131 Padova, Italy
| | - Stefania Sut
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Italy
| | - Stefano Dall'Acqua
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Italy
| | - Paola Braghetta
- Department of Molecular Medicine, University of Padova, 35131 Padova, Italy
| | - Carlo Semenza
- ERN Neuromuscular Center, Department of Neurosciences, University of Padova, 35129 Padova, Italy.,IRCCS San Camillo Hospital, 30126 Venice, Italy
| | - Elena Pegoraro
- ERN Neuromuscular Center, Department of Neurosciences, University of Padova, 35129 Padova, Italy
| | - Francesco Papaleo
- Genetics of Cognition Laboratory, Neuroscience Area, Istituto Italiano di Tecnologia, 16163, Genova, Italy
| | - Paolo Bonaldo
- Department of Molecular Medicine, University of Padova, 35131 Padova, Italy
| | - Matilde Cescon
- Department of Molecular Medicine, University of Padova, 35131 Padova, Italy
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Yang Y, Lewis MM, Kong L, Mailman RB. A Dopamine D 1 Agonist Versus Methylphenidate in Modulating Prefrontal Cortical Working Memory. J Pharmacol Exp Ther 2022; 382:88-99. [PMID: 35661631 PMCID: PMC9341252 DOI: 10.1124/jpet.122.001215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/17/2022] [Indexed: 11/22/2022] Open
Abstract
Methylphenidate is used widely to treat symptoms of attention-deficit/hyperactivity disorder (ADHD), but like other stimulants has significant side effects. This study used a rodent model (spontaneously hypertensive rat) of spatial working memory (sWM) to compare the effects of methylphenidate with the novel dopamine D1-like receptor agonist 2-methyldihydrexidine. Acute oral administration of methylphenidate (1.5 mg/kg) caused sWM improvement in half of the tested rats, but impairment in the others. Both improvement or impairment were eliminated by administration of the D1 antagonist SCH39266 directly into the prefrontal cortex (PFC). Conversely, 2-methyldihydrexidine showed greater sWM improvement compared with methylphenidate without significant impairment in any subject. Its effects correlated negatively with vehicle-treated baseline performance (i.e., rats with lower baseline performance improved more than rats with higher baseline performance). These behavioral effects were associated with neural activities in the PFC. Single neuron firing rate was changed, leading to the alteration in neuronal preference to correct or error behavioral responses. Overall, 2-methyldihydrexidine was superior to methylphenidate in decreasing the neuronal preference, prospectively, in the animals whose behavior was improved. In contrast, methylphenidate, but not 2-methyldihydrexidine, significantly decreased neuronal preference, retrospectively, in those animals who had impaired performance. These results suggest that a D1 agonist may be more effective than methylphenidate in regulating sWM-related behavior through neural modulation of the PFC, and thus may be superior to methylphenidate or other stimulants as ADHD pharmacotherapy. SIGNIFICANCE STATEMENT: Methylphenidate is effective in ADHD by its indirect agonist stimulation of dopamine and/or adrenergic receptors, but the precise effects on specific targets are unclear. This study compared methylphenidate to a dopamine D1 receptor-selective agonist by investigating effects on working memory occurring via neural modulation in the prefrontal cortex. The data suggest that pharmacological treatment selectively targeting the dopamine D1 may offer a superior approach to ADHD pharmacotherapy.
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Affiliation(s)
- Yang Yang
- Department of Pharmacology (Y.Y., M.M.L., R.B.M.), Department of Neurology (M.M.L., R.B.M.), and Department of Public Health Sciences (L.K.), Penn State University College of Medicine, Hershey, Pennsylvania
| | - Mechelle M Lewis
- Department of Pharmacology (Y.Y., M.M.L., R.B.M.), Department of Neurology (M.M.L., R.B.M.), and Department of Public Health Sciences (L.K.), Penn State University College of Medicine, Hershey, Pennsylvania
| | - Lan Kong
- Department of Pharmacology (Y.Y., M.M.L., R.B.M.), Department of Neurology (M.M.L., R.B.M.), and Department of Public Health Sciences (L.K.), Penn State University College of Medicine, Hershey, Pennsylvania
| | - Richard B Mailman
- Department of Pharmacology (Y.Y., M.M.L., R.B.M.), Department of Neurology (M.M.L., R.B.M.), and Department of Public Health Sciences (L.K.), Penn State University College of Medicine, Hershey, Pennsylvania
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Marino RA, Gaprielian P, Levy R. Systemic D1-R and D2-R antagonists in Non-Human Primates Differentially Impact Learning and Memory While Impairing Motivation and Motor Performance. Eur J Neurosci 2022; 56:4121-4140. [PMID: 35746869 DOI: 10.1111/ejn.15743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/14/2022] [Accepted: 06/15/2022] [Indexed: 11/30/2022]
Abstract
Dopamine (DA) modulates cognition in part via differential activation of D1 and D2 receptors within the striatum and prefrontal cortex, yet evidence for cognitive impairments stemming from DA blockade or deficiency is inconsistent. Given the predominance of D1 over D2 receptors (R) in the prefrontal cortex of primates, D1-R blockade should more strongly influence frontal executive function (including working memory), while D2-R blockade should impair processes more strongly associated with the dorsal striatum (including cognitive flexibility, and learning). To test how systemic DA blockade disrupts cognition, we administered D1-R and D2-R like antagonists to healthy monkeys while they performed a series of cognitive tasks. Two selective DA receptor antagonist drugs (SCH-23390 hydrochloride: D1/D5-R antagonist; or Eticlopride hydrochloride: D2/D3-R antagonist) or placebo (0.9% saline) were systemically administered. Four tasks were used: (1) 'visually guided reaching', to test response time and accuracy, (2) 'reversal learning', to test association learning and attention, (3) 'self-ordered sequential search' to test spatial working memory, and (4) 'delayed match to sample' to test object working memory. Increased reach response times and decreased motivation to work for liquid reward was observed with both the D1/D5-R and D2/D3-R antagonists at the maximum dosages that still enabled task performance. The D2/D3-R antagonist impaired performance in the reversal learning task, while object and spatial working memory performance was not consistently affected in the tested tasks for either drug. These results are consistent with the theory that systemic D2/D3-R antagonists preferentially influence striatum processes (cognitive flexibility) while systemic D1/D5-R administration is less detrimental to frontal executive function.
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Affiliation(s)
- Robert A Marino
- Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.,Department of Surgery, Kingston General Hospital, Kingston, Ontario, Canada
| | - Pauline Gaprielian
- Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
| | - Ron Levy
- Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.,Department of Surgery, Kingston General Hospital, Kingston, Ontario, Canada
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31
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Yang Y, Kocher SD, Lewis MM, Mailman RB. Dose-Dependent Regulation on Prefrontal Neuronal Working Memory by Dopamine D1 Agonists: Evidence of Receptor Functional Selectivity-Related Mechanisms. Front Neurosci 2022; 16:898051. [PMID: 35784852 PMCID: PMC9244699 DOI: 10.3389/fnins.2022.898051] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
Low doses of dopamine D1 agonists improve working memory-related behavior, but high doses eliminate the improvement, thus yielding an ‘inverted-U’ dose-response curve. This dose-dependency also occurs at the single neuron level in the prefrontal cortex where the cellular basis of working memory is represented. Because signaling mechanisms are unclear, we examined this process at the neuron population level. Two D1 agonists (2-methyldihydrexidine and CY208,243) having different signaling bias were tested in rats performing a spatial working memory-related T-maze task. 2-Methyldihydrexidine is slightly bias toward D1-mediated β-arrestin-related signaling as it is a full agonist at adenylate cyclase and a super-agonist at β-arrestin recruitment, whereas CY208,243 is slightly bias toward D1-mediated cAMP signaling as it has relatively high intrinsic activity at adenylate cyclase, but is a partial agonist at β-arrestin recruitment. Both compounds had the expected inverted U dose-dependency in modulating prefrontal neuronal activities, albeit with important differences. Although CY208,243 was superior in improving the strength of neuronal outcome sensitivity to the working memory-related choice behavior in the T-maze, 2-methyldihydrexidine better reduced neuron-to-neuron variation. Interestingly, at the neuron population level, both drugs affected the percentage, uniformity, and ensemble strength of neuronal sensitivity in a complicated dose-dependent fashion, but the overall effect suggested higher efficiency and potency of 2-methyldihydrexidine compared to CY208,243. The differences between 2-methyldihydrexidine and CY208,243 may be related to their specific D1 signaling. These results suggest that D1-related dose-dependent regulation of working memory can be modified differentially by functionally selective ligands, theoretically increasing the balance between desired and undesired effects.
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Affiliation(s)
- Yang Yang
- Department of Pharmacology, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States
- Translational Brain Research Center, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States
- *Correspondence: Yang Yang,
| | - Susan D. Kocher
- Department of Pharmacology, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States
| | - Mechelle M. Lewis
- Department of Pharmacology, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States
- Translational Brain Research Center, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States
- Department of Neurology, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States
| | - Richard B. Mailman
- Department of Pharmacology, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States
- Translational Brain Research Center, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States
- Department of Neurology, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States
- Richard B. Mailman,
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32
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Nordin K, Gorbach T, Pedersen R, Panes Lundmark V, Johansson J, Andersson M, McNulty C, Riklund K, Wåhlin A, Papenberg G, Kalpouzos G, Bäckman L, Salami A. DyNAMiC: A prospective longitudinal study of dopamine and brain connectomes: A new window into cognitive aging. J Neurosci Res 2022; 100:1296-1320. [PMID: 35293013 PMCID: PMC9313590 DOI: 10.1002/jnr.25039] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 01/18/2022] [Accepted: 02/16/2022] [Indexed: 11/07/2022]
Abstract
Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age-related cognitive decline is crucial in promoting healthy aging. Here, we present the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5-year longitudinal study spanning the adult human lifespan. DyNAMiC examines age-related changes in the brain's structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age-sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20-80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the [11 C]SCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with [11 C]raclopride PET measuring D2DR. Age-related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u-shaped association between D1DR and resting-state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age-related cognitive decline.
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Affiliation(s)
- Kristin Nordin
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Department of Integrative Medical BiologyUmeå UniversityUmeåSweden
- Wallenberg Centre for Molecular MedicineUmeå UniversityUmeåSweden
- Present address:
Aging Research CenterKarolinska Institutet & Stockholm UniversityStockholm11330Sweden
| | - Tetiana Gorbach
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Department of Integrative Medical BiologyUmeå UniversityUmeåSweden
- Wallenberg Centre for Molecular MedicineUmeå UniversityUmeåSweden
- Umeå School of Business, Economics and StatisticsUmeå UniversityUmeåSweden
| | - Robin Pedersen
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Department of Integrative Medical BiologyUmeå UniversityUmeåSweden
- Wallenberg Centre for Molecular MedicineUmeå UniversityUmeåSweden
| | - Vania Panes Lundmark
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Department of Integrative Medical BiologyUmeå UniversityUmeåSweden
| | - Jarkko Johansson
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Wallenberg Centre for Molecular MedicineUmeå UniversityUmeåSweden
- Department of Radiation SciencesUmeå UniversityUmeåSweden
| | - Micael Andersson
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Department of Integrative Medical BiologyUmeå UniversityUmeåSweden
| | - Charlotte McNulty
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Department of Integrative Medical BiologyUmeå UniversityUmeåSweden
- Wallenberg Centre for Molecular MedicineUmeå UniversityUmeåSweden
| | - Katrine Riklund
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Department of Radiation SciencesUmeå UniversityUmeåSweden
| | - Anders Wåhlin
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Department of Radiation SciencesUmeå UniversityUmeåSweden
| | - Goran Papenberg
- Aging Research CenterKarolinska Institutet & Stockholm UniversityStockholmSweden
| | - Grégoria Kalpouzos
- Aging Research CenterKarolinska Institutet & Stockholm UniversityStockholmSweden
| | - Lars Bäckman
- Aging Research CenterKarolinska Institutet & Stockholm UniversityStockholmSweden
| | - Alireza Salami
- Umeå Center for Functional Brain Imaging (UFBI)Umeå UniversityUmeåSweden
- Department of Integrative Medical BiologyUmeå UniversityUmeåSweden
- Wallenberg Centre for Molecular MedicineUmeå UniversityUmeåSweden
- Aging Research CenterKarolinska Institutet & Stockholm UniversityStockholmSweden
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Palavicino-Maggio CB, Sengupta S. The Neuromodulatory Basis of Aggression: Lessons From the Humble Fruit Fly. Front Behav Neurosci 2022; 16:836666. [PMID: 35517573 PMCID: PMC9062135 DOI: 10.3389/fnbeh.2022.836666] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/07/2022] [Indexed: 11/22/2022] Open
Abstract
Aggression is an intrinsic trait that organisms of almost all species, humans included, use to get access to food, shelter, and mating partners. To maximize fitness in the wild, an organism must vary the intensity of aggression toward the same or different stimuli. How much of this variation is genetic and how much is externally induced, is largely unknown but is likely to be a combination of both. Irrespective of the source, one of the principal physiological mechanisms altering the aggression intensity involves neuromodulation. Any change or variation in aggression intensity is most likely governed by a complex interaction of several neuromodulators acting via a meshwork of neural circuits. Resolving aggression-specific neural circuits in a mammalian model has proven challenging due to the highly complex nature of the mammalian brain. In that regard, the fruit fly model Drosophila melanogaster has provided insights into the circuit-driven mechanisms of aggression regulation and its underlying neuromodulatory basis. Despite morphological dissimilarities, the fly brain shares striking similarities with the mammalian brain in genes, neuromodulatory systems, and circuit-organization, making the findings from the fly model extremely valuable for understanding the fundamental circuit logic of human aggression. This review discusses our current understanding of how neuromodulators regulate aggression based on findings from the fruit fly model. We specifically focus on the roles of Serotonin (5-HT), Dopamine (DA), Octopamine (OA), Acetylcholine (ACTH), Sex Peptides (SP), Tachykinin (TK), Neuropeptide F (NPF), and Drosulfakinin (Dsk) in fruit fly male and female aggression.
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Affiliation(s)
- Caroline B Palavicino-Maggio
- Basic Neuroscience Division, Department of Psychiatry, Harvard Medical School, McLean Hospital, Boston, MA, United States.,Department of Neurobiology, Harvard Medical School, Boston, MA, United States
| | - Saheli Sengupta
- Basic Neuroscience Division, Department of Psychiatry, Harvard Medical School, McLean Hospital, Boston, MA, United States
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34
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Per2 Expression Regulates the Spatial Working Memory of Mice through DRD1-PKA-CREB Signaling. Mol Neurobiol 2022; 59:4292-4303. [PMID: 35508866 DOI: 10.1007/s12035-022-02845-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 04/20/2022] [Indexed: 10/18/2022]
Abstract
Several individuals worldwide show cognitive impairment due to various reasons, including a prolonged lifespan and an altered lifestyle. Various causes, such as broken circadian rhythms and dopamine-related factors, have been proposed to be involved in the development of cognitive impairment. However, the underlying pathways remain elusive. Humans with circadian misalignment often face cognitive impairments, and animals with mutations in circadian rhythm-related genes display impaired cognitive functions. To analyze this in detail, this study aimed to investigate the pathways potentially involved in cognitive impairment using Period2 (Per2) transgenic animals. Spatial working memory performance in Per2 knockout (KO) and wild-type mice was assessed using the Barnes maze and Y-maze. The dopamine-related protein expression levels in the hippocampus were measured by Western blotting and enzyme-linked immunosorbent assay (ELISA). Per2 KO mice exhibited impaired spatial working memory, and the expression levels of dopamine receptor D1 (DRD1), protein kinase A (PKA), and cAMP response element-binding protein (CREB) were higher in Per2 KO mice than in control mice. Additionally, DRD1 expression levels were inversely proportional to those of PER2. Thus, memory tests were again conducted after administration of the DRD1 antagonist SCH-23390. Per2 KO mice recovered from memory impairment, and the levels of PKA and CREB decreased after treatment. The effects of Aβ on memory in Per2 mice were also investigated, and we found the increased Aβ levels did not influence the memory performance of Per2 mice after SCH-23390 treatment. These results indicate that Per2 expression levels might influence spatial working memory performance via DRD1-PKA-CREB-dependent signaling.
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35
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van Kempen J, Brandt C, Distler C, Bellgrove MA, Thiele A. Dopamine influences attentional rate modulation in Macaque posterior parietal cortex. Sci Rep 2022; 12:6914. [PMID: 35484302 PMCID: PMC9050696 DOI: 10.1038/s41598-022-10634-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 04/11/2022] [Indexed: 11/23/2022] Open
Abstract
Cognitive neuroscience has made great strides in understanding the neural substrates of attention, but our understanding of its neuropharmacology remains incomplete. Although dopamine has historically been studied in relation to frontal functioning, emerging evidence suggests important dopaminergic influences in parietal cortex. We recorded single- and multi-unit activity whilst iontophoretically administering dopaminergic agonists and antagonists while rhesus macaques performed a spatial attention task. Out of 88 units, 50 revealed activity modulation by drug administration. Dopamine inhibited firing rates according to an inverted-U shaped dose-response curve and increased gain variability. D1 receptor antagonists diminished firing rates according to a monotonic function and interacted with attention modulating gain variability. Finally, both drugs decreased the pupil light reflex. These data show that dopamine shapes neuronal responses and modulates aspects of attentional processing in parietal cortex.
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Affiliation(s)
- Jochem van Kempen
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
| | - Christian Brandt
- Research Unit for ORL - Head and Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark
- University of Southern Denmark, Odense, Denmark
| | - Claudia Distler
- Allgemeine Zoologie Und Neurobiologie, Ruhr-Universität Bochum, 44801, Bochum, Germany
| | - Mark A Bellgrove
- Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, VIC, 3800, Australia
| | - Alexander Thiele
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
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36
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Lee J, Kim C, Lee KC. An Empirical Approach to Analyzing the Effects of Stress on Individual Creativity in Business Problem-Solving: Emphasis on the Electrocardiogram, Electroencephalogram Methodology. Front Psychol 2022; 13:705442. [PMID: 35391973 PMCID: PMC8983065 DOI: 10.3389/fpsyg.2022.705442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 02/21/2022] [Indexed: 11/25/2022] Open
Abstract
In this study, experiments were conducted on 30 subjects by means of electrocardiogram (ECG) and electroencephalogram (EEG) methodologies as well as a money game to examine the effects of stress on creativity in business problem-solving. The study explained the relationship between creativity and human physiological response using the biopsychosocial model of challenge and threat. The subjects were asked to perform a cognitive mapping task. Based on the brain wave theory, we identified the types of brain waves and locations of brain activities that occurred during the creative problem-solving process in a business environment and studied the effects of stress on creativity. The results of the experiments showed significant differences in creativity in business problem-solving depending on whether or not stress was triggered. Differences were found in the time domain (SDNN, RMSSD) and frequency domain (HF, LF/HF ratio) of heart rates, a physiological stress indicator, between the stress group and the no-stress group. A brain wave analysis confirmed that alpha waves increased in the frontal lobe of the brain during creative business problem-solving but decreased when the subjects were under stress, during which beta waves in the brain increased. This study seeks to examine creativity in business problem-solving by studying the effects of stress on human physiological response and cognitive functions in the hope of providing a new and objective interpretation of existing research results.
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Affiliation(s)
- Jungwoo Lee
- SKK Business School, Sungkyunkwan University, Seoul, South Korea
| | - Cheong Kim
- SKK Business School, Sungkyunkwan University, Seoul, South Korea
- Economics Department, Airports Council International (ACI) World, Montreal, QC, Canada
| | - Kun Chang Lee
- SKK Business School, Sungkyunkwan University, Seoul, South Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, South Korea
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37
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Polli FS, Kohlmeier KA. Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence. World J Psychiatry 2022; 12:212-235. [PMID: 35317337 PMCID: PMC8900586 DOI: 10.5498/wjp.v12.i2.212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 08/07/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.
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Affiliation(s)
- Filip S Polli
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristi A Kohlmeier
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
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38
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Xu L, Feng J, Yu L. Avalanche criticality in individuals, fluid intelligence, and working memory. Hum Brain Mapp 2022; 43:2534-2553. [PMID: 35146831 PMCID: PMC9057106 DOI: 10.1002/hbm.25802] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/23/2022] [Indexed: 02/06/2023] Open
Abstract
The critical brain hypothesis suggests that efficient neural computation can be achieved through critical brain dynamics. However, the relationship between human cognitive performance and scale‐free brain dynamics remains unclear. In this study, we investigated the whole‐brain avalanche activity and its individual variability in the human resting‐state functional magnetic resonance imaging (fMRI) data. We showed that though the group‐level analysis was inaccurate because of individual variability, the subject wise scale‐free avalanche activity was significantly associated with maximal synchronization entropy of their brain activity. Meanwhile, the complexity of functional connectivity, as well as structure–function coupling, is maximized in subjects with maximal synchronization entropy. We also observed order–disorder phase transitions in resting‐state brain dynamics and found that there were longer times spent in the subcritical regime. These results imply that large‐scale brain dynamics favor the slightly subcritical regime of phase transition. Finally, we showed evidence that the neural dynamics of human participants with higher fluid intelligence and working memory scores are closer to criticality. We identified brain regions whose critical dynamics showed significant positive correlations with fluid intelligence performance and found that these regions were located in the prefrontal cortex and inferior parietal cortex, which were believed to be important nodes of brain networks underlying human intelligence. Our results reveal the possible role that avalanche criticality plays in cognitive performance and provide a simple method to identify the critical point and map cortical states on a spectrum of neural dynamics, ranging from subcriticality to supercriticality.
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Affiliation(s)
- Longzhou Xu
- School of Physical Science and Technology, Lanzhou University, Lanzhou, China
| | - Jianfeng Feng
- Institute of Science and Technology for Brain Inspired Intelligence, Fudan University, Shanghai, China.,Department of Computer Science, University of Warwick, Coventry, UK.,School of Mathematical Sciences, School of Life Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China
| | - Lianchun Yu
- School of Physical Science and Technology, Lanzhou University, Lanzhou, China.,Lanzhou Center for Theoretical Physics, Key Laboratory of Theoretical Physics of Gansu Province, Lanzhou University, Lanzhou, China.,The School of Nationalities' Educators, Qinghai Normal University, Xining, China
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39
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Sotoyama H, Inaba H, Iwakura Y, Namba H, Takei N, Sasaoka T, Nawa H. The dual role of dopamine in the modulation of information processing in the prefrontal cortex underlying social behavior. FASEB J 2022; 36:e22160. [DOI: 10.1096/fj.202101637r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/12/2021] [Accepted: 12/29/2021] [Indexed: 01/08/2023]
Affiliation(s)
- Hidekazu Sotoyama
- Department of Molecular Neurobiology Brain Research Institute, Niigata University Niigata Japan
| | - Hiroyoshi Inaba
- Department of Molecular Neurobiology Brain Research Institute, Niigata University Niigata Japan
| | - Yuriko Iwakura
- Department of Molecular Neurobiology Brain Research Institute, Niigata University Niigata Japan
- Department of Brain Tumor Biology Brain Research Institute, Niigata University Niigata Japan
| | - Hisaaki Namba
- Department of Molecular Neurobiology Brain Research Institute, Niigata University Niigata Japan
- Department of Physiological Sciences, School of Pharmaceutical Sciences Wakayama Medical University Wakayama Japan
| | - Nobuyuki Takei
- Department of Molecular Neurobiology Brain Research Institute, Niigata University Niigata Japan
- Department of Brain Tumor Biology Brain Research Institute, Niigata University Niigata Japan
| | - Toshikuni Sasaoka
- Department of Comparative & Experimental Medicine Brain Research Institute, Niigata University Niigata Japan
| | - Hiroyuki Nawa
- Department of Molecular Neurobiology Brain Research Institute, Niigata University Niigata Japan
- Department of Physiological Sciences, School of Pharmaceutical Sciences Wakayama Medical University Wakayama Japan
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40
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Jones-Tabah J, Mohammad H, Paulus EG, Clarke PBS, Hébert TE. The Signaling and Pharmacology of the Dopamine D1 Receptor. Front Cell Neurosci 2022; 15:806618. [PMID: 35110997 PMCID: PMC8801442 DOI: 10.3389/fncel.2021.806618] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 12/23/2021] [Indexed: 12/30/2022] Open
Abstract
The dopamine D1 receptor (D1R) is a Gαs/olf-coupled GPCR that is expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, and cognitive processes. Although the D1R was initially identified as a promising drug target almost 40 years ago, the development of clinically useful ligands has until recently been hampered by a lack of suitable candidate molecules. The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders. To develop better therapeutics, advances in ligand chemistry must be matched by an expanded understanding of D1R signaling across cell populations in the brain, and in disease states. Depending on the brain region, the D1R couples primarily to either Gαs or Gαolf through which it activates a cAMP/PKA-dependent signaling cascade that can regulate neuronal excitability, stimulate gene expression, and facilitate synaptic plasticity. However, like many GPCRs, the D1R can signal through multiple downstream pathways, and specific signaling signatures may differ between cell types or be altered in disease. To guide development of improved D1R ligands, it is important to understand how signaling unfolds in specific target cells, and how this signaling affects circuit function and behavior. In this review, we provide a summary of D1R-directed signaling in various neuronal populations and describe how specific pathways have been linked to physiological and behavioral outcomes. In addition, we address the current state of D1R drug development, including the pharmacology of newly developed non-catecholamine ligands, and discuss the potential utility of D1R-agonists in Parkinson's Disease and cognitive impairment.
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41
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Cools R, Arnsten AFT. Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine. Neuropsychopharmacology 2022; 47:309-328. [PMID: 34312496 PMCID: PMC8617291 DOI: 10.1038/s41386-021-01100-8] [Citation(s) in RCA: 96] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/06/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023]
Abstract
The primate prefrontal cortex (PFC) subserves our highest order cognitive operations, and yet is tremendously dependent on a precise neurochemical environment for proper functioning. Depletion of noradrenaline and dopamine, or of acetylcholine from the dorsolateral PFC (dlPFC), is as devastating as removing the cortex itself, and serotonergic influences are also critical to proper functioning of the orbital and medial PFC. Most neuromodulators have a narrow inverted U dose response, which coordinates arousal state with cognitive state, and contributes to cognitive deficits with fatigue or uncontrollable stress. Studies in monkeys have revealed the molecular signaling mechanisms that govern the generation and modulation of mental representations by the dlPFC, allowing dynamic regulation of network strength, a process that requires tight regulation to prevent toxic actions, e.g., as occurs with advanced age. Brain imaging studies in humans have observed drug and genotype influences on a range of cognitive tasks and on PFC circuit functional connectivity, e.g., showing that catecholamines stabilize representations in a baseline-dependent manner. Research in monkeys has already led to new treatments for cognitive disorders in humans, encouraging future research in this important field.
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Affiliation(s)
- Roshan Cools
- Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Amy F T Arnsten
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
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Torrisi SA, Geraci F, Contarini G, Salomone S, Drago F, Leggio GM. Dopamine D3 Receptor, Cognition and Cognitive Dysfunctions in Neuropsychiatric Disorders: From the Bench to the Bedside. Curr Top Behav Neurosci 2022; 60:133-156. [PMID: 35435642 DOI: 10.1007/7854_2022_326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The dopamine D3 receptor (D3R) plays a prominent role in the modulation of cognition in healthy individuals, as well as in the pathophysiological mechanism underlying the cognitive deficits affecting patients suffering from neuropsychiatric disorders. At a therapeutic level, a growing body of evidence suggests that the D3R blockade enhances cognitive and thus it may be an optimal therapeutic strategy against cognitive dysfunctions. However, this is not always the case because other ligands targeting the D3R, and behaving as partial agonists or biased agonists, may exert their pro-cognitive effect by maintaining adequate level of dopamine in key brain areas tuning cognitive performances. In this chapter, we review and discuss preclinical and clinical findings with the aim to remark the crucial role of the D3R in cognition and to strengthen the message that drugs targeting D3R may be excellent cognitive enhancers for the treatment of several neuropsychiatric and neurological disorders.
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Affiliation(s)
| | - Federica Geraci
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Gabriella Contarini
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Salomone Salomone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Gian Marco Leggio
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
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Pignalosa FC, Desiderio A, Mirra P, Nigro C, Perruolo G, Ulianich L, Formisano P, Beguinot F, Miele C, Napoli R, Fiory F. Diabetes and Cognitive Impairment: A Role for Glucotoxicity and Dopaminergic Dysfunction. Int J Mol Sci 2021; 22:ijms222212366. [PMID: 34830246 PMCID: PMC8619146 DOI: 10.3390/ijms222212366] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/09/2021] [Accepted: 11/13/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsible for the onset of several long-term complications. Recent evidence suggests that cognitive dysfunction represents an emerging complication of DM, but the underlying molecular mechanisms are still obscure. Dopamine (DA), a neurotransmitter essentially known for its relevance in the regulation of behavior and movement, modulates cognitive function, too. Interestingly, alterations of the dopaminergic system have been observed in DM. This review aims to offer a comprehensive overview of the most relevant experimental results assessing DA’s role in cognitive function, highlighting the presence of dopaminergic dysfunction in DM and supporting a role for glucotoxicity in DM-associated dopaminergic dysfunction and cognitive impairment. Several studies confirm a role for DA in cognition both in animal models and in humans. Similarly, significant alterations of the dopaminergic system have been observed in animal models of experimental diabetes and in diabetic patients, too. Evidence is accumulating that advanced glycation end products (AGEs) and their precursor methylglyoxal (MGO) are associated with cognitive impairment and alterations of the dopaminergic system. Further research is needed to clarify the molecular mechanisms linking DM-associated dopaminergic dysfunction and cognitive impairment and to assess the deleterious impact of glucotoxicity.
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Affiliation(s)
- Francesca Chiara Pignalosa
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
| | - Antonella Desiderio
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
| | - Paola Mirra
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
| | - Cecilia Nigro
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
| | - Giuseppe Perruolo
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
| | - Luca Ulianich
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
| | - Pietro Formisano
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
| | - Francesco Beguinot
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
| | - Claudia Miele
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
- Correspondence: ; Tel.: +39-081-746-3248
| | - Raffaele Napoli
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
| | - Francesca Fiory
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.C.P.); (A.D.); (P.M.); (C.N.); (G.P.); (L.U.); (P.F.); (F.B.); (R.N.); (F.F.)
- URT “Genomic of Diabetes”, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy
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A pair of dopamine neurons mediate chronic stress signals to induce learning deficit in Drosophila melanogaster. Proc Natl Acad Sci U S A 2021; 118:2023674118. [PMID: 34654742 DOI: 10.1073/pnas.2023674118] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2021] [Indexed: 11/18/2022] Open
Abstract
Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster The chronic stress-induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc>α/β neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress-induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.
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Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments. Int J Mol Sci 2021; 22:ijms22189905. [PMID: 34576069 PMCID: PMC8468549 DOI: 10.3390/ijms22189905] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 01/09/2023] Open
Abstract
Schizophrenia is a major mental illness characterized by positive and negative symptoms, and by cognitive deficit. Although cognitive impairment is disabling for patients, it has been largely neglected in the treatment of schizophrenia. There are several reasons for this lack of treatments for cognitive deficit, but the complexity of its etiology-in which neuroanatomic, biochemical and genetic factors concur-has contributed to the lack of effective treatments. In the last few years, there have been several attempts to develop novel drugs for the treatment of cognitive impairment in schizophrenia. Despite these efforts, little progress has been made. The latest findings point to the importance of developing personalized treatments for schizophrenia which enhance neuroplasticity, and of combining pharmacological treatments with non-pharmacological measures.
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Abi-Dargham A, Javitch JA, Slifstein M, Anticevic A, Calkins ME, Cho YT, Fonteneau C, Gil R, Girgis R, Gur RE, Gur RC, Grinband J, Kantrowitz J, Kohler C, Krystal J, Murray J, Ranganathan M, Santamauro N, Van Snellenberg J, Tamayo Z, Wolf D, TRANSCENDS Group
D’SouzaDeepakSrihariVinodGueorguievaRalitzaPatelPrashantForselius-BielenKimberleeLuJingButlerAudreyFramGeenaAfriyie-AgyemangYvetteSelloniAlexandriaCadavidLauraGomez-LunaSandraGuptaAartiRadhakrishnanRajivRashidAliAkerRyanAbrahimPhilishaBassir NiaAnahitaSurtiToralKegelesLawrence SCarlsonMarleneGoldbergTerryGangwischJamesBenedictErinneGovilPreetikaBrazisStephanieMayerMegande la GarrigueNathalieFallonNatalkaBaumvollTopazAbeykoonSameeraPerlmanGregBobchinKellyElliottMarkSchmidtLyndsayRushSagePortAllisonHeffernanZacLaneyNinaKantorJennaHohingThomas, Gray D, Lieberman J. Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia. Schizophr Bull 2021; 48:199-210. [PMID: 34423843 PMCID: PMC8781338 DOI: 10.1093/schbul/sbab095] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.
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Affiliation(s)
- Anissa Abi-Dargham
- Department of Psychiatry, Stony Brook Renaissance School of Medicine, Stony Brook, NY, USA,Department of Psychiatry, New York State Psychaitric Institute, Columbia University, New York, NY, USA,Department of Psychiatry, Yale University, New Haven, CT, USA,Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA,Cerevel Therapeutics Research and Development, Boston, MA, USA,To whom correspondence should be addressed; Tel: +(631) 885-0814; e-mail:
| | - Jonathan A Javitch
- Department of Psychiatry, New York State Psychaitric Institute, Columbia University, New York, NY, USA
| | - Mark Slifstein
- Department of Psychiatry, Stony Brook Renaissance School of Medicine, Stony Brook, NY, USA
| | - Alan Anticevic
- Department of Psychiatry, Yale University, New Haven, CT, USA
| | - Monica E Calkins
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Youngsun T Cho
- Department of Psychiatry, Yale University, New Haven, CT, USA
| | - Clara Fonteneau
- Department of Psychiatry, Yale University, New Haven, CT, USA
| | - Roberto Gil
- Department of Psychiatry, Stony Brook Renaissance School of Medicine, Stony Brook, NY, USA
| | - Ragy Girgis
- Department of Psychiatry, New York State Psychaitric Institute, Columbia University, New York, NY, USA
| | - Raquel E Gur
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ruben C Gur
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jack Grinband
- Department of Psychiatry, New York State Psychaitric Institute, Columbia University, New York, NY, USA
| | - Joshua Kantrowitz
- Department of Psychiatry, New York State Psychaitric Institute, Columbia University, New York, NY, USA
| | - Christian Kohler
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - John Krystal
- Department of Psychiatry, Yale University, New Haven, CT, USA
| | - John Murray
- Department of Psychiatry, Yale University, New Haven, CT, USA
| | | | | | - Jared Van Snellenberg
- Department of Psychiatry, Stony Brook Renaissance School of Medicine, Stony Brook, NY, USA
| | - Zailyn Tamayo
- Department of Psychiatry, Yale University, New Haven, CT, USA
| | - Daniel Wolf
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - David Gray
- Cerevel Therapeutics Research and Development, Boston, MA, USA
| | - Jeffrey Lieberman
- Department of Psychiatry, New York State Psychaitric Institute, Columbia University, New York, NY, USA
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Turk AZ, Lotfi Marchoubeh M, Fritsch I, Maguire GA, SheikhBahaei S. Dopamine, vocalization, and astrocytes. BRAIN AND LANGUAGE 2021; 219:104970. [PMID: 34098250 PMCID: PMC8260450 DOI: 10.1016/j.bandl.2021.104970] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 05/21/2021] [Accepted: 05/23/2021] [Indexed: 05/06/2023]
Abstract
Dopamine, the main catecholamine neurotransmitter in the brain, is predominately produced in the basal ganglia and released to various brain regions including the frontal cortex, midbrain and brainstem. Dopamine's effects are widespread and include modulation of a number of voluntary and innate behaviors. Vigilant regulation and modulation of dopamine levels throughout the brain is imperative for proper execution of motor behaviors, in particular speech and other types of vocalizations. While dopamine's role in motor circuitry is widely accepted, its unique function in normal and abnormal speech production is not fully understood. In this perspective, we first review the role of dopaminergic circuits in vocal production. We then discuss and propose the conceivable involvement of astrocytes, the numerous star-shaped glia cells of the brain, in the dopaminergic network modulating normal and abnormal vocal productions.
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Affiliation(s)
- Ariana Z Turk
- Neuron-Glia Signaling and Circuits Unit, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, 20892 MD, USA
| | - Mahsa Lotfi Marchoubeh
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, 72701 AR, USA
| | - Ingrid Fritsch
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, 72701 AR, USA
| | - Gerald A Maguire
- Department of Psychiatry and Neuroscience, School of Medicine, University of California, Riverside, 92521 CA, USA
| | - Shahriar SheikhBahaei
- Neuron-Glia Signaling and Circuits Unit, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, 20892 MD, USA.
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The effects of aging and dopaminergic inhibition on large scale maze learning in rhesus monkeys. Brain Res Bull 2021; 175:63-68. [PMID: 34274430 DOI: 10.1016/j.brainresbull.2021.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/26/2021] [Accepted: 07/13/2021] [Indexed: 11/24/2022]
Abstract
Studies have shown that both aging and dopaminergic dysfunction affected spatial learning and memory. Systematic dopaminergic inhibition, by dopamine receptor (DR) antagonist treatment, impaired spatial delayed-response (SDR) performance, which mostly requires self/body centered egocentric reference frame, in rhesus monkeys. However, the influence of DR blocking on large scale maze learning, which mainly involves world centered allocentric reference frame, remains unclear. Moreover, the effects of aging on the process also remain unknown. Present study investigated the issues, using large scale mazes composed of 8 maze units. Maze No. 1 was used for adaptation and training. Mazes No. 2-4 were used to investigate influence of aging, by comparing learning performance between young and aged rhesus monkeys. Mazes No. 5-8 were used to investigate the effects of DR antagonist treatment, SKF-83566 (0.02, 0.2 mg/kg) and haloperidol (0.001, 0.01 mg/kg). The result showed similar learning performance between young and aged monkeys in mazes No. 2-4. In mazes No. 5-8, we also found similar learning performance after acute DR antagonist injection, compared with pre-treatment baseline performance in mazes No. 2-4, in both young and aged groups. The result showed similar maze learning performance between young and aged monkeys in mazes (No. 2-4), suggesting no significant influence of aging on allocentric spatial learning. We also found similar maze performance in both groups, after dopamine receptor antagonist treatment in mazes (No. 5-8) compared with pre-treatment baseline performance in mazes (No. 2-4), suggesting no significant influence of dopaminergic inhibition on allocentric spatial learning. Together, the present study potentially suggested insensitivity of allocentric spatial learning to cognitive aging and acute systematic dopaminergic inhibition.
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Hori Y, Nagai Y, Mimura K, Suhara T, Higuchi M, Bouret S, Minamimoto T. D1- and D2-like receptors differentially mediate the effects of dopaminergic transmission on cost-benefit evaluation and motivation in monkeys. PLoS Biol 2021; 19:e3001055. [PMID: 34197448 PMCID: PMC8248602 DOI: 10.1371/journal.pbio.3001055] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 05/27/2021] [Indexed: 11/29/2022] Open
Abstract
It has been widely accepted that dopamine (DA) plays a major role in motivation, yet the specific contribution of DA signaling at D1-like receptor (D1R) and D2-like receptor (D2R) to cost–benefit trade-off remains unclear. Here, by combining pharmacological manipulation of DA receptors (DARs) and positron emission tomography (PET) imaging, we assessed the relationship between the degree of D1R/D2R blockade and changes in benefit- and cost-based motivation for goal-directed behavior of macaque monkeys. We found that the degree of blockade of either D1R or D2R was associated with a reduction of the positive impact of reward amount and increasing delay discounting. Workload discounting was selectively increased by D2R antagonism. In addition, blocking both D1R and D2R had a synergistic effect on delay discounting but an antagonist effect on workload discounting. These results provide fundamental insight into the distinct mechanisms of DA action in the regulation of the benefit- and cost-based motivation, which have important implications for motivational alterations in both neurological and psychiatric disorders. Using quantitatively controlled pharmacological manipulations, this study teases apart the role of D1- and D2-like dopamine receptors in motivation and goal-directed behavior in monkeys, revealing complementary roles of two dopamine receptor subtypes in the computation of the cost/benefit trade-off to guide action.
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Affiliation(s)
- Yukiko Hori
- Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Yuji Nagai
- Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Koki Mimura
- Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Tetsuya Suhara
- Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Makoto Higuchi
- Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Sebastien Bouret
- Team Motivation Brain & Behavior, Institut du Cerveau et de la Moelle épinière (ICM), Centre National de la Recherche Scientifique (CNRS), Hôpital Pitié Salpêtrière, Paris, France
| | - Takafumi Minamimoto
- Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
- * E-mail:
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50
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McCarthy CI, Chou-Freed C, Rodríguez SS, Yaneff A, Davio C, Raingo J. Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons. J Gen Physiol 2021; 152:151624. [PMID: 32259196 PMCID: PMC7201881 DOI: 10.1085/jgp.201912492] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 02/14/2020] [Accepted: 03/12/2020] [Indexed: 01/19/2023] Open
Abstract
Alterations in dopamine receptor type 1 (D1R) density are associated with cognitive deficits of aging and schizophrenia. In the prefrontal cortex (PFC), D1R plays a critical role in the regulation of working memory, which is impaired in these cognitive deficit states, but the cellular events triggered by changes in D1R expression remain unknown. A previous report demonstrated that interaction between voltage-gated calcium channel type 2.2 (CaV2.2) and D1R stimulates CaV2.2 postsynaptic surface location in medial PFC pyramidal neurons. Here, we show that in addition to the occurrence of the physical receptor-channel interaction, constitutive D1R activity mediates up-regulation of functional CaV2.2 surface density. We performed patch-clamp experiments on transfected HEK293T cells and wild-type C57BL/6 mouse brain slices, as well as imaging experiments and cAMP measurements. We found that D1R coexpression led to ∼60% increase in CaV2.2 currents in HEK293T cells. This effect was occluded by preincubation with a D1/D5R inverse agonist, chlorpromazine, and by replacing D1R with a D1R mutant lacking constitutive activity. Moreover, D1R-induced increase in CaV2.2 currents required basally active Gs protein, as well as D1R-CaV2.2 interaction. In mice, intraperitoneal administration of chlorpromazine reduced native CaV currents’ sensitivity to ω-conotoxin-GVIA and their size by ∼49% in layer V/VI pyramidal neurons from medial PFC, indicating a selective effect on CaV2.2. Additionally, we found that reducing D1/D5R constitutive activity correlates with a decrease in the agonist-induced D1/D5R inhibitory effect on native CaV currents. Our results could be interpreted as a stimulatory effect of D1R constitutive activity on the number of CaV2.2 channels available for dopamine-mediated modulation. Our results contribute to the understanding of the physiological role of D1R constitutive activity and may explain the noncanonical postsynaptic distribution of functional CaV2.2 in PFC neurons.
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Affiliation(s)
- Clara Inés McCarthy
- Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology, Universidad Nacional de La Plata, Consejo de Investigaciones Científicas y Técnicas, Comisión de Investigaciones de la Provincia de Buenos Aires, Buenos Aires, Argentina
| | - Cambria Chou-Freed
- Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology, Universidad Nacional de La Plata, Consejo de Investigaciones Científicas y Técnicas, Comisión de Investigaciones de la Provincia de Buenos Aires, Buenos Aires, Argentina
| | - Silvia Susana Rodríguez
- Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology, Universidad Nacional de La Plata, Consejo de Investigaciones Científicas y Técnicas, Comisión de Investigaciones de la Provincia de Buenos Aires, Buenos Aires, Argentina
| | - Agustín Yaneff
- Instituto de Investigaciones Farmacológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carlos Davio
- Instituto de Investigaciones Farmacológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jesica Raingo
- Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology, Universidad Nacional de La Plata, Consejo de Investigaciones Científicas y Técnicas, Comisión de Investigaciones de la Provincia de Buenos Aires, Buenos Aires, Argentina
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